Combination therapy using azabicyclo compound for cancer

ABSTRACT

Provided is a novel method for treating cancer using an HSP90 inhibitor which exhibits a markedly superior antitumor effect and has a reduced side effect. 
     An antitumor agent is characterized in that an azabicyclo compound of the following Formula (1) or a salt thereof is administered in combination with other antitumor agent(s).

TECHNICAL FIELD

The present invention relates to an antitumor agent containing acombination of an azabicyclo compound or a salt thereof and otherantitumor agent(s), and an antitumor effect potentiator for otherantitumor agent(s).

BACKGROUND ART

A group of proteins called molecular chaperons is a multifunctionalprotein, which promotes the formation of the functional structures ofother proteins or maintains these structures, promotes correctassociation, inhibits unnecessary aggregation, protects other proteinsfrom degradation, and promotes secretion (Non Patent Literature 1).HSP90 is a molecular chaperon as abundant as approximately 1 to 2% ofall intracellular soluble proteins and is however unnecessary for thebiosynthesis of the majority of polypeptides, unlike other chaperonproteins (Non Patent Literature 1). Signaling-related factors (forexample, ERBB1/EGFR, ERBB2/HER2, MET, IGF1R, KDR/VEGFR, FLT3, ZAP70,KIT, CHUK/IKK, BRAF, RAF1, SRC, and AKT), cell cycle regulators (forexample, CDK4, CDK6, Cyclin D, PLK1, and BIRC5), and transcriptionalregulators (for example, HIF-1α, p53, androgen receptor, estrogenreceptor, and progesterone receptor) are known as the main clientproteins whose structure formation or stability is regulated by HSP90through the interaction therebetween (Non Patent Literatures 2 and 3).HSP90 is deeply involved in cell proliferation or survival bymaintaining the normal functions of these proteins. Furthermore, HSP90is required for the normal functions of mutated or chimeric factors (forexample, BCR-ABL and NPM-ALK) which cause carcinogenesis or exacerbationof cancer. This indicates the importance of HSP90 particularly forprocesses such as carcinogenesis, cancer survival, growth, exacerbation,and metastasis (Non Patent Literature 2).

The inhibition of the chaperon functions of HSP90 by specific inhibitorssuch as geldanamycin causes the inactivation, destabilization, anddegradation of the client proteins, resulting in induction of a halt incell proliferation or apoptosis (Non Patent Literature 4). In terms ofthe physiological functions of HSP90, HSP90 inhibitors are characterizedin that they can simultaneously inhibit multiple signaling pathwaysinvolved in cancer survival and growth. Thus, the HSP90 inhibitors canserve as pharmaceuticals having extensive and effective anticanceractivity. Moreover, from the findings that cancer cell-derived HSP90 hashigher activity and higher affinity for ATP or inhibitors than those ofnormal cell-derived HSP90, it has been expected that the HSP90inhibitors would serve as pharmaceuticals having high cancer selectivity(Non Patent Literature 5). Currently, the clinical development ofmultiple HSP90 inhibitors as anticancer agents is ongoing. The mostadvancing Ganetespib is under development as single agents as well asunder test on the combined use with other antitumor agents such asdocetaxel (Non Patent Literature 6).

Further, a new type of HSP90 inhibitor has been reported (PatentLiterature 1), and HSP90 inhibitors with higher antitumor effects andreduced side effects have been desired.

CITATION LIST Patent Literature

-   Patent Literature 1: WO 2011/004610 A

Non Patent Literatures

-   Non Patent Literature 1: Nature Reviews Cancer 5, 761-772(2005)-   Non Patent Literature 2: TRENDS in Molecular Medicine 10(6),    283-290(2004)-   Non Patent Literature 3: Clin Can Res 15, 9-14(2009)-   Non Patent Literature 4: Current Opinion in Pharmacology 8,    370-374(2008)-   Non Patent Literature 5: Drug Resistance Updates 12, 17-27(2009)-   Non Patent Literature 6: Invest New Drugs. 30(6):2201-9(2012)

SUMMARY OF INVENTION Technical Problem

An object of the invention is to provide a method of using HSP90inhibitors with high antitumor effects and reduced side effects.

Solution to Problem

The present inventors examined combined use of various HSP90 inhibitorsand other antitumor agent(s) under the circumstances. As a result, theyfound that an azabicyclo compound having an HSP90 inhibitory agentremarkably potentiates the antitumor effect of extremely various rangesof antitumor agents having different action mechanisms.

That is, the invention provides the following [1] to [36].

[1] An antitumor agent, where an azabicyclo compound of the followingFormula (I) or a salt thereof:

in the formula, X¹ represents CH or N;

any one of X², X³, and X⁴ is N, and the others represent CH;

any one or two of Y¹, Y², Y³, and Y⁴ are C—R⁴, and the others are thesame or different and represent CH or N;

R¹ represents an optionally substituted mono- or bi-cyclic unsaturatedheterocyclic group having 1 to 4 of heteroatom selected from the groupconsisting of N, S, and O;

R² represents a hydrogen atom, an optionally substituted alkyl grouphaving 1 to 6 of carbon atom, or an optionally substituted alkenyl grouphaving 2 to 6 of carbon atom;

R³ represents a cyano group or —CO—R⁵;

R⁴(s) are the same or different and represent a hydrogen atom, a halogenatom, a cyano group, an optionally substituted alkyl group having 1 to 6of carbon atom, an alkenyl group having 2 to 6 of carbon atom, an alkoxygroup having 1 to 6 of carbon atom, an aromatic hydrocarbon group,—N(R⁶)(R⁷), —S—R⁸, or —CO—R⁹;

R⁵ represents an amino group optionally having a hydroxyl group or anoptionally substituted mono- or di-alkylamino group;

R⁶ and R⁷ are the same or different and represent a hydrogen atom, anoptionally substituted alkyl group having 1 to 6 of carbon atom, ahalogenoalkyl group having 1 to 6 of carbon atom, an optionallysubstituted cycloalkyl group having 3 to 7 of carbon atom, an optionallysubstituted aralkyl group, an optionally substituted aromatichydrocarbon group, an optionally substituted saturated heterocyclicgroup, or an optionally substituted unsaturated heterocyclic group, orR⁶ and R⁷ optionally form a saturated heterocyclic group together with anitrogen atom to which they are bonded;

R⁸ represents an optionally substituted cycloalkyl group having 3 to 7of carbon atom or an optionally substituted aromatic hydrocarbon group;and

R⁹ represents a hydrogen atom, a hydroxyl group, an amino groupoptionally having a hydroxyl group, or an optionally substituted mono-or di-alkylamino group, is administered in combination with otherantitumor agent(s).

[2] The antitumor agent according to [1], where

the azabicyclo compound is a compound of Formula (I),

in the formula, X¹ is CH or N;

X² is N and X³ and X⁴ are CH;

Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other isCH;

R¹ is any of an optionally substituted 1H-imidazol-1-yl group, anoptionally substituted pyrazol-4-yl group, an optionally substitutedthiophen-3-yl group, an optionally substituted furan-2-yl group, anoptionally substituted pyridin-3-yl group, an optionally substitutedpyridin-4-yl group, an optionally substituted indol-5-yl group, anoptionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, anoptionally substituted benzofuran-2-yl group, an optionally substitutedquinolin-3-yl group, and an optionally substituted5,6,7,8-tetrahydroquinolin-3-yl group;

R² is an alkyl group having 1 to 6 of carbon atom optionally having ahalogen atom or an alkenyl group having 2 to 6 of carbon atom;

R³ is —CO—R⁵;

R⁴ is a halogen atom, an alkyl group having 1 to 6 of carbon atomoptionally having a mono- or di-(C1-C6 alkyl)amino group or a monocyclic5- to 7-membered saturated heterocyclic group having one or two of anyheteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom,—N(R⁶)(R⁷), —SR⁸, or —CO—R⁹;

R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group;

R⁶ is a hydrogen atom or an optionally substituted alkyl group having 1to 6 of carbon atom;

R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to6 of carbon atom, an optionally substituted cycloalkyl group having 3 to7 of carbon atom, an optionally substituted aralkyl group having 7 to 12of carbon atom, an optionally substituted aromatic hydrocarbon grouphaving 6 to 14 of carbon atom, an optionally substituted mono- orbi-cyclic saturated heterocyclic group having 1 to 4 of heteroatomselected from the group consisting of N, S, and O, or an optionallysubstituted mono- or bi-cyclic unsaturated heterocyclic group having 1to 4 of heteroatom selected from the group consisting of N, S, and O, orR⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic group togetherwith a nitrogen atom to which they are bonded;

R⁸ is an optionally substituted cycloalkyl group having 3 to 7 of carbonatom or an optionally substituted aromatic hydrocarbon group having 6 to14 of carbon atom; and

R⁹ is a hydrogen atom, a hydroxyl group, an amino group, or a mono- ordi-(C1-C6 alkyl)amino group.

[3] The antitumor agent according to [1] or [2], where the azabicyclocompound is3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide.

[4] The antitumor agent according to any one of [1] to [3], where theother antitumor agent is one or more of kind(s) selected from the groupconsisting of an antitumor antibiotic substance, a platinum-based agent,a pyrimidine-based antimetabolite agent, a purine-based antimetaboliteagent, a folic acid antimetabolite agent, a plant alkaloid-basedantitumor agent, an immunomodulating drug, and a low molecular weightmolecular targeted drug.

[5] The antitumor agent according to any one of [1] to [4], where theother antitumor agent is one or more of kind(s) selected from the groupconsisting of amrubicin, doxorubicin, cisplatin, oxaliplatin,gemcitabine, cytarabine, pemetrexed, paclitaxel (for example, TAXOL orABRAXANE), docetaxel, etoposide, lenalidomide, imatinib, gefitinib,dasatinib, erlotinib, lapatinib, and crizotinib.

[6] The antitumor agent according to any one of [1] to [5], where theazabicyclo compound or a salt thereof and the other antitumor agent areadministered to a cancer patient simultaneously or separately at aninterval.

[7] An antitumor effect potentiator for other antitumor agent(s),containing an azabicyclo compound or a salt thereof, in which

the azabicyclo compound is a compound of the following Formula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, and R¹ to R³ are as defined above.

[8] An antitumor agent containing an azabicyclo compound or a saltthereof, which is used for treating a cancer patient who has beenadministered other antitumor agent (s), in which

the azabicyclo compound is an azabicyclo compound of the followingFormula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[9] An antitumor agent containing a combination of an azabicyclocompound or a salt thereof and other antitumor agent(s), in which

the azabicyclo compound is an azabicyclo compound of the followingFormula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[10] An azabicyclo compound of the following Formula (I) or a saltthereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for treating a tumor by administration in combination withother antitumor agent(s).

[11] The compound according to [10] or a salt thereof, where

the azabicyclo compound is a compound of Formula (I),

in the formula, X¹ is CH or N;

X² is N and X³ and X⁴ are CH;

Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other isCH;

R¹ is any of an optionally substituted 1H-imidazol-1-yl group, anoptionally substituted pyrazol-4-yl group, an optionally substitutedthiophen-3-yl group, an optionally substituted furan-2-yl group, anoptionally substituted pyridin-3-yl group, an optionally substitutedpyridin-4-yl group, an optionally substituted indol-5-yl group, anoptionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, anoptionally substituted benzofuran-2-yl group, an optionally substitutedquinolin-3-yl group, and an optionally substituted5,6,7,8-tetrahydroquinolin-3-yl group;

R² is an alkyl group having 1 to 6 of carbon atom optionally having ahalogen atom or an alkenyl group having 2 to 6 of carbon atom;

R³ is —CO—R⁵;

R⁴ is a halogen atom, an alkyl group having 1 to 6 of carbon atomoptionally having a mono- or di-(C1-C6 alkyl)amino group or a monocyclic5- to 7-membered saturated heterocyclic group having one or two of anyheteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom,—N(R⁶)(R⁷), —SR⁸, or —CO—R⁹;

R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group;

R⁶ is a hydrogen atom or an optionally substituted alkyl group having 1to 6 of carbon atom;

R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to6 of carbon atom, an optionally substituted cycloalkyl group having 3 to7 of carbon atom, an optionally substituted aralkyl group having 7 to 12of carbon atom, an optionally substituted aromatic hydrocarbon grouphaving 6 to 14 of carbon atom, an optionally substituted mono- orbi-cyclic saturated heterocyclic group having 1 to 4 of heteroatomselected from the group consisting of N, S, and O, or an optionallysubstituted mono- or bi-cyclic unsaturated heterocyclic group having 1to 4 of heteroatom selected from the group consisting of N, S, and O, orR⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic group togetherwith a nitrogen atom to which they are bonded;

R⁸ is an optionally substituted cycloalkyl group having 3 to 7 of carbonatom or an optionally substituted aromatic hydrocarbon group having 6 to14 of carbon atom; and

R⁹ is a hydrogen atom, a hydroxyl group, an amino group, or a mono- ordi-(C1-C6 alkyl)amino group.

[12] The compound according to [10] or [11] or a salt thereof, where theazabicyclo compound is3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide.

[13] The compound according to any one of [10] to [12] or a saltthereof, where the other antitumor agent is one or more of kind(s)selected from the group consisting of an antitumor antibiotic substance,a platinum-based agent, a pyrimidine-based antimetabolite agent, apurine-based antimetabolite agent, a folic acid antimetabolite agent, aplant alkaloid-based antitumor agent, an immunomodulating drug, and alow molecular weight molecular targeted drug.

[14] The compound according to any one of [10] to [13] or a saltthereof, where the other antitumor agent is one or more of kind(s)selected from the group consisting of amrubicin, doxorubicin, cisplatin,oxaliplatin, gemcitabine, cytarabine, pemetrexed, paclitaxel (forexample, TAXOL or ABRAXANE), docetaxel, etoposide, lenalidomide,imatinib, gefitinib, dasatinib, erlotinib, lapatinib, and crizotinib.

[15] The compound according to any one of [10] to [14] or a saltthereof, where the azabicyclo compound or a salt thereof and the otherantitumor agent are administered to a cancer patient simultaneously orseparately at an interval.

[16]A compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for potentiating the antitumor effect of other antitumoragent(s).

[17] An azabicyclo compound of the following Formula (I) or a saltthereof, which is used for treating a cancer patient who has beenadministered other antitumor agent(s):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[18] An azabicyclo compound of the following Formula (I) or a saltthereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for treating a tumor in combination with other antitumoragent(s).

[19] Use of an azabicyclo compound of the following Formula (I) or asalt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for producing an antitumor agent to be administered incombination with other antitumor agent(s).

[20] The use according to [19], where

the azabicyclo compound is a compound of Formula (I),

in the formula, X¹ is CH or N;

X² is N and X³ and X⁴ are CH;

Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other isCH;

R¹ is any of an optionally substituted 1H-imidazol-1-yl group, anoptionally substituted pyrazol-4-yl group, an optionally substitutedthiophen-3-yl group, an optionally substituted furan-2-yl group, anoptionally substituted pyridin-3-yl group, an optionally substitutedpyridin-4-yl group, an optionally substituted indol-5-yl group, anoptionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, anoptionally substituted benzofuran-2-yl group, an optionally substitutedquinolin-3-yl group, and an optionally substituted5,6,7,8-tetrahydroquinolin-3-yl group;

R² is an alkyl group having 1 to 6 of carbon atom optionally having ahalogen atom or an alkenyl group having 2 to 6 of carbon atom;

R³ is —CO—R⁵;

R⁴ is a halogen atom, an alkyl group having 1 to 6 of carbon atomoptionally having a mono- or di-(C1-C6 alkyl)amino group or a monocyclic5- to 7-membered saturated heterocyclic group having one or two of anyheteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom,—N(R⁶)(R⁷), —SR⁸, or —CO—R⁹;

R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group;

R⁶ is a hydrogen atom or an optionally substituted alkyl group having 1to 6 of carbon atom;

R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to6 of carbon atom, an optionally substituted cycloalkyl group having 3 to7 of carbon atom, an optionally substituted aralkyl group having 7 to 12of carbon atom, an optionally substituted aromatic hydrocarbon grouphaving 6 to 14 of carbon atom, an optionally substituted mono- orbi-cyclic saturated heterocyclic group having 1 to 4 of heteroatomselected from the group consisting of N, S, and O, or an optionallysubstituted mono- or bi-cyclic unsaturated heterocyclic group having 1to 4 of heteroatom selected from the group consisting of N, S, and O, orR⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic group togetherwith a nitrogen atom to which they are bonded;

R⁸ is an optionally substituted cycloalkyl group having 3 to 7 of carbonatom or an optionally substituted aromatic hydrocarbon group having 6 to14 of carbon atom; and

R⁹ is a hydrogen atom, a hydroxyl group, an amino group, or a mono- ordi-(C1-C6 alkyl)amino group.

[21] The use according to [19] or [20], where the azabicyclo compound is3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide.

[22] The use according to any one of [19] to [21], where the otherantitumor agent is one or more of kind(s) selected from the groupconsisting of an antitumor antibiotic substance, a platinum-based agent,a pyrimidine-based antimetabolite agent, a purine-based antimetaboliteagent, a folic acid antimetabolite agent, a plant alkaloid-basedantitumor agent, an immunomodulating drug, and a low molecular weightmolecular targeted drug.

[23] The use according to any one of [19] to [22], where the otherantitumor agent is one or more of kind(s) selected from the groupconsisting of amrubicin, doxorubicin, cisplatin, oxaliplatin,gemcitabine, cytarabine, pemetrexed, paclitaxel (for example, TAXOL orABRAXANE), docetaxel, etoposide, lenalidomide, imatinib, gefitinib,dasatinib, erlotinib, lapatinib, and crizotinib.

[24] The use according to any one of [19] to [23], where the azabicyclocompound or a salt thereof and the other antitumor agent areadministered to a cancer patient simultaneously or separately at aninterval.

[25] Use of a compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for producing an antitumor effect potentiator for otherantitumor agent(s).

[26] Use of an azabicyclo compound of the following Formula (I) or asalt thereof:

in the formula, X¹ to X⁴, Y¹ to Y, R¹ to R³ are as defined above,

which is used for producing an antitumor agent for treating a cancerpatient who has been administered other antitumor agent (s).

[27] Use of an azabicyclo compound of the following Formula (I) or asalt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for producing an antitumor agent by combining otherantitumor agent(s).

[28]A method for treating a tumor, including administrating anazabicyclo compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

and other antitumor agent(s), in combination.

[29] The treating method according to [28], where

the azabicyclo compound is a compound of Formula (I),

in the formula, X¹ is CH or N;

X² is N and X³ and X⁴ are CH;

Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other isCH;

R¹ is any of an optionally substituted 1H-imidazol-1-yl group, anoptionally substituted pyrazol-4-yl group, an optionally substitutedthiophen-3-yl group, an optionally substituted furan-2-yl group, anoptionally substituted pyridin-3-yl group, an optionally substitutedpyridin-4-yl group, an optionally substituted indol-5-yl group, anoptionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, anoptionally substituted benzofuran-2-yl group, an optionally substitutedquinolin-3-yl group, and an optionally substituted5,6,7,8-tetrahydroquinolin-3-yl group;

R² is an alkyl group having 1 to 6 of carbon atom optionally having ahalogen atom or an alkenyl group having 2 to 6 of carbon atom;

R³ is —CO—R⁵;

R⁴ is a halogen atom, an alkyl group having 1 to 6 of carbon atomoptionally having a mono- or di-(C1-C6 alkyl)amino group or a monocyclic5- to 7-membered saturated heterocyclic group having one or two of anyheteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom,—N(R⁶)(R⁷), —SR⁸, or —CO—R⁹;

R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group;

R⁶ is a hydrogen atom or an optionally substituted alkyl group having 1to 6 of carbon atom;

R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to6 of carbon atom, an optionally substituted cycloalkyl group having 3 to7 of carbon atom, an optionally substituted aralkyl group having 7 to 12of carbon atom, an optionally substituted aromatic hydrocarbon grouphaving 6 to 14 of carbon atom, an optionally substituted mono- orbi-cyclic saturated heterocyclic group having 1 to 4 of heteroatomselected from the group consisting of N, S, and O, or an optionallysubstituted mono- or bi-cyclic unsaturated heterocyclic group having 1to 4 of heteroatom selected from the group consisting of N, S, and O, orR⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic group togetherwith a nitrogen atom to which they are bonded;

R⁸ is an optionally substituted cycloalkyl group having 3 to 7 of carbonatom or an optionally substituted aromatic hydrocarbon group having 6 to14 of carbon atom; and

R⁹ is a hydrogen atom, a hydroxyl group, an amino group, or a mono- ordi-(C1-C6 alkyl)amino group.

[30] The treating method according to [28], where the azabicyclocompound is3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide.

[31] The treating method according to [28], where the other antitumoragent is one or more of kind(s) selected from the group consisting of anantitumor antibiotic substance, a platinum-based agent, apyrimidine-based antimetabolite agent, a purine-based antimetaboliteagent, a folic acid antimetabolite agent, a plant alkaloid-basedantitumor agent, an immunomodulating drug, and a low molecular weightmolecular targeted drug.

[32] The treating method according to [28], where the other antitumoragent is one or more of kind(s) selected from the group consisting ofamrubicin, doxorubicin, cisplatin, oxaliplatin, gemcitabine, cytarabine,pemetrexed, paclitaxel (for example, TAXOL or ABRAXANE), docetaxel,etoposide, lenalidomide, imatinib, gefitinib, dasatinib, erlotinib,lapatinib, and crizotinib.

[33] The treating method according to any one of [28] to [32], where theazabicyclo compound or a salt thereof and the other antitumor agent areadministered to a cancer patient simultaneously or separately at aninterval.

[34]A method for potentiating the antitumor effect of other antitumoragent(s), including administering an azabicyclo compound or a saltthereof, in which

the azabicyclo compound is a compound of the following Formula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[35]A method for treating a tumor, including administering an azabicyclocompound or a salt thereof to a cancer patient who has been administeredother antitumor agent(s), in which

the azabicyclo compound is an azabicyclo compound of the followingFormula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[36]A method for treating a tumor, including administering an azabicyclocompound or a salt thereof and other antitumor agent(s), in combination,in which

the azabicyclo compound is an azabicyclo compound of the followingFormula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

Advantageous Effects of Invention

The antitumor agent of the invention serves to perform cancer therapyexhibiting high antitumor effect while suppressing side effects, and,thus, the survival of a cancer patient can be prolonged.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an effect of the combination of Compound 1 and docetaxelwith respect to the rate of tumor growth of a human non-small cell lungcancer line NCI-H2170.

FIG. 2 shows an effect of the combination of Compound 1 and paclitaxelwith respect to the rate of tumor growth of a human non-small cell lungcancer line NCI-H441.

FIG. 3 shows an effect of the combination of Compound 1 and cisplatinwith respect to the rate of tumor growth of a human stomach cancer lineNCI-N87.

FIG. 4 shows an effect of the combination of Compound 1 and amrubicinwith respect to the rate of tumor growth of a human small cell lungcancer cell line SBC-1.

DESCRIPTION OF EMBODIMENTS

The HSP90 inhibitor in the invention, which provides an excellentsynergic effect with other antitumor agent(s), is an azabicyclo compoundof the following Formula (I) and a salt thereof.

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

In the present specification, examples of “substituents” include ahalogen atom, a hydroxyl group, a cyano group, a nitro group, an alkylgroup, a halogenoalkyl group, a cycloalkyl group, a cycloalkyl-alkylgroup, an aralkyl group, a hydroxyalkyl group, an alkenyl group, analkynyl group, an alkoxy group, a halogenoalkoxy group, an alkoxy-alkylgroup, a cycloalkoxy group, a cycloalkyl-alkoxy group, an aralkyloxygroup, an aralkyloxy-alkyl group, an alkylthio group, acycloalkyl-alkylthio group, an amino group, a mono- or dialkylaminogroup, a cycloalkyl-alkylamino group, an acyl group, an acyloxy group,an oxo group, a carboxyl group, an alkoxycarbonyl group, anaralkyloxycarbonyl group, a carbamoyl group, a saturated or unsaturatedheterocyclic group, an aromatic hydrocarbon group, and a saturatedheterocyclic oxy group. When the above substituent is present, thenumber of the substituents is typically 1 to 3.

Examples of the halogen atom included in the substituents include achlorine atom, a bromine atom, a fluorine atom, and an iodine atom.

The alkyl group or the halogenoalkyl group included in the substituentspreferably refers to a linear or branched alkyl group having 1 to 6 ofcarbon atom or a group in which one or all hydrogen atom(s) in such analkyl group are substituted by the halogen atom described above.Examples thereof include alkyl groups such as a methyl group, an ethylgroup, an n-propyl group, an isopropyl group, an n-butyl group, anisobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group,and a hexyl group and halogenoalkyl groups such as a trifluoromethylgroup.

The cycloalkyl group included in the substituents is preferably acycloalkyl group having 3 to 7 of carbon atom, and examples thereofinclude a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, acyclohexyl group, and a cycloheptyl group.

The cycloalkyl-alkyl group included in the substituents is preferably analkyl group having 1 to 6 of carbon atom which is substituted bycycloalkyl having 3 to 7 of carbon atom, and examples thereof include acyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylmethylgroup, a cyclopentylmethyl group, and a cyclohexylmethyl group.

The aralkyl group included in the substituents preferably refers to alinear or branched alkyl group having 1 to 6 of carbon atom which issubstituted by an aromatic hydrocarbon group having 6 to 14 of carbonatom, and examples thereof include a benzyl group, a phenylethyl group,a phenylpropyl group, a naphthylmethyl group, and a naphthylethyl group.

The hydroxyalkyl group included in the substituents preferably refers tothe linear or branched alkyl group having 1 to 6 of carbon atomdescribed which has a hydroxy group, and examples thereof include ahydroxymethyl group and a hydroxyethyl group.

The alkenyl group included in the substituents preferably refers to analkenyl group having 2 to 6 of carbon atom which contains acarbon-carbon double bond, and examples thereof include a vinyl group,an allyl group, a methylvinyl group, a propenyl group, a butenyl group,a pentenyl group, and a hexenyl group.

The alkynyl group included in the substituents preferably refers to analkynyl group having 2 to 6 of carbon atom which contains acarbon-carbon triple bond, and examples thereof include an ethynyl groupand a propargyl group.

The alkoxy group or the halogenoalkoxy group included in thesubstituents preferably refers to a linear or branched alkoxy grouphaving 1 to 6 of carbon atom, or a group in which such an alkoxy groupis substituted by the halogen atom described above, and examples thereofinclude a methoxy group, an ethoxy group, an n-propoxy group, anisopropoxy group, a 1-methylpropoxy group, an n-butoxy group, anisobutoxy group, a tert-butoxy group, a 2-methyl-butoxy group, aneopentyloxy group, a pentan-2-yloxy group, a fluoromethoxy group, adifluoromethoxy group, a trifluoromethoxy group, a 1,1-difluoroethoxygroup, a 2,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, a1,1,2,2-tetrafluoroethoxy group, a perfluoroethoxy group, a3-fluoro-2-(fluoromethyl)-propoxy group, a 1,3-difluoropropan-2-yloxygroup, and a 2,2,3,3,3-pentafluoro-1-propoxy group.

The cycloalkoxy group included in the substituents is preferably acycloalkoxy group having 3 to 7 of carbon atom, and examples thereofinclude a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxygroup, a cyclohexyloxy group, and a cycloheptyloxy group.

The alkoxy-alkyl group included in the substituents preferably refers tothe alkyl group having 1 to 6 of carbon atom described above which issubstituted by the linear or branched alkoxy group having 1 to 6 ofcarbon atom described above, and examples thereof include amethoxymethyl group and an ethoxymethyl group.

The cycloalkyl-alkoxy group included in the substituents is preferablyan alkoxy group having 1 to 6 of carbon atom which is substituted bycycloalkyl having 3 to 7 of carbon atom, and examples thereof include acyclopropylmethoxy group, a cyclopropylethoxy group, a cyclobutylmethoxygroup, a cyclopentylmethoxy group, and a cyclohexylmethoxy group.

The aralkyloxy group included in the substituents preferably refers toan oxy group which has the aralkyl group described above, and examplesthereof include a benzyloxy group, a phenethyloxy group, aphenylpropyloxy group, a naphthylmethyloxy group, and a naphthylethyloxygroup.

The aralkyloxy-alkyl group included in the substituents preferablyrefers to the linear or branched alkyl group having 1 to 6 of carbonatom described above which has the aralkyloxy group described above, andexamples thereof include a benzyloxymethyl group and a benzyloxyethylgroup.

The alkylthio group included in the substituents is preferably a (C1-C6)alkylthio group which refers to a linear or branched alkylthio grouphaving 1 to 6 of carbon atom, and examples thereof include a methylthiogroup, an ethylthio group, an n-propylthio group, an isopropylthiogroup, an n-butylthio group, an isobutylthio group, a sec-butylthiogroup, a tert-butylthio group, a pentylthio group, and a hexylthiogroup.

The cycloalkyl-alkylthio group included in the substituents ispreferably an alkylthio group having 1 to 6 of carbon atom which issubstituted by cycloalkyl having 3 to 7 of carbon atom, and examplesthereof include a cyclopropylmethylthio group, a cyclopropylethylthiogroup, a cyclobutylmethylthio group, a cyclopentylmethylthio group, anda cyclohexylmethylthio group.

The mono- or dialkylamino group included in the substituents is a mono-or di-(C1-C6 alkyl)amino group which refers to an amino group which ismonosubstituted or disubstituted by the linear or branched alkyl grouphaving 1 to 6 of carbon atom described above, and examples thereofinclude a methylamino group, a dimethylamino group, an ethylamino group,a diethylamino group, and a methylethylamino group.

The cycloalkyl-alkylamino group included in the substituents refers toan alkylamino group which is substituted by the cycloalkyl groupdescribed above, and examples thereof include a cyclopropylmethylaminogroup, a cyclobutylmethylamino group, and a cyclopentylmethylaminogroup.

Examples of the acyl group included in the substituents include: linearor branched acyl groups having 1 to 6 of carbon atom such as a formylgroup, an acetyl group, a propionyl group, an n-butyryl group, anisobutyryl group, a valeryl group, an isovaleryl group, and a pivaloylgroup; and a benzoyl group.

Examples of the acyloxy group included in the substituents include:linear or branched acyloxy groups having 1 to 6 of carbon atom such as aformyloxy group, an acetoxy group, a propionyloxy group, an n-butyryloxygroup, an isobutyryloxy group, a valeryloxy group, an isovaleryloxygroup, and a pivaloyloxy group; a benzoyloxy group; and aminoacid-derived acyloxy groups such as a glycyloxy group, an alanyloxygroup, and a leucyloxy group.

The alkoxycarbonyl group included in the substituents refers to acarbonyl group which is substituted by the alkoxy group described above,and examples thereof include a methoxycarbonyl group, an ethoxycarbonylgroup, an n-propoxycarbonyl group, an isopropoxycarbonyl group, a1-methylpropoxycarbonyl group, an n-butoxycarbonyl group, anisobutoxycarbonyl group, a tert-butoxycarbonyl group, a2-methyl-butoxycarbonyl group, a neopentyloxycarbonyl group, and apentan-2-yloxycarbonyl group.

The aralkyloxycarbonyl group included in the substituents preferablyrefers to a carbonyl group which is substituted by the aralkyloxy groupdescribed above, and examples thereof include a benzyloxycarbonyl group,a phenethyloxycarbonyl group, a phenylpropyloxycarbonyl group, anaphthylmethyloxycarbonyl group, and a naphthylethyloxycarbonyl group.

Examples of the carbamoyl group in the substituents include a —CONH₂group, a (mono- or dialkyl)carbamoyl group, a (mono- or diaryl)carbamoylgroup, an (N-alkyl-N-aryl)carbamoyl group, a pyrrolidinocarbamoyl group,a piperidinocarbamoyl group, a piperazinocarbamoyl group, and amorpholinocarbamoyl group.

The saturated or unsaturated heterocyclic group included in thesubstituents refers to a mono- or bi-cyclic saturated or 5- to10-membered unsaturated heterocyclic group preferably having 1 to 4 ofany heteroatom of N, S and O, and examples thereof include apyrrolidinyl group, a piperidinyl group, a piperazinyl group, ahexamethyleneimino group, a morpholino group, a thiomorpholino group, ahomopiperazinyl group, a tetrahydrofuranyl group, a tetrahydropyranylgroup, an imidazolyl group, a thienyl group, a furyl group, a pyrrolylgroup, an oxazolyl group, an isoxazolyl group, a thiazolyl group, anisothiazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolylgroup, a pyridyl group, a pyrazyl group, a pyrimidinyl group, apyridazinyl group, an indolyl group, an isoindolyl group, an indazolylgroup, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, abenzofuranyl group, a dihydrobenzofuranyl group, a benzoimidazolylgroup, a benzooxazolyl group, a benzothiazolyl group, a purinyl group, aquinolyl group, an isoquinolyl group, a quinazolinyl group, and aquinoxalyl group.

The aromatic hydrocarbon group included in the substituents preferablyrefers to an aromatic hydrocarbon group having 6 to 14 of carbon atom,and examples thereof include a phenyl group and a naphthyl group.

The saturated heterocyclic oxy group included in the substituents refersto a monocyclic 5- to 7-membered saturated heterocyclic group having oneor two of any heteroatom of N, S and O, for example, an oxy group whichhas a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, ahexamethyleneimino group, a morpholino group, a thiomorpholino group, ora homopiperazinyl group. Examples thereof include a tetrahydrofuranyloxygroup and a tetrahydropyranyloxy group.

In Formula (I), X¹ represents CH or N. Moreover, in Formula (I), any oneof X², X³, and X⁴ represents N, and the others represent CH. Based onthese definitions of X¹ to X⁴, examples of the azabicyclo skeleton inFormula (I) include the following structures:

in the formula, R¹ and R² are as defined above.

Among these skeletons, (A-3) and (A-6) are particularly preferable.

In Formula (I), the “mono- or bi-cyclic unsaturated heterocyclic grouphaving 1 to 4 of heteroatom selected from the group consisting of N, S,and O” in the “optionally substituted mono- or bi-cyclic unsaturatedheterocyclic group having 1 to 4 of heteroatom selected from the groupconsisting of N, S, and O” represented by R¹ is preferably a mono- orbi-cyclic 5- to 10-membered unsaturated heterocyclic group having 1 to 3of heteroatom selected from the group consisting of N, S, and O, morepreferably a monocyclic 5- to 6-membered unsaturated heterocyclic grouphaving 1 to 3 of heteroatom selected from the group consisting of N, S,and O, or a bicyclic 9- to 10-membered unsaturated heterocyclic grouphaving 1 to 3 of heteroatom selected from the group consisting of N, S,and O. The heterocyclic group is preferably a group having imidazole,pyrazole, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole,isothiazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine,pyridazine, indole, isoindole, pyrrolopyridine, indazole,methylenedioxyphenyl, ethylenedioxyphenyl, benzofuran,dihydrobenzofuran, benzimidazol, benzoxazol, benzothiazole, purine,quinoline, tetrahydroquinoline, isoquinoline, quinazoline, orquinoxaline, more preferably a group having imidazol, pyrazol,thiophene, furan, pyridine, indole, pyrrolopyridine, benzofuran,quinoline, or tetrahydroquinoline, and particularly preferably a grouphaving imidazol, pyridine, or quinoline.

specific examples thereof include a 1H-imidazol-1-yl group, a1H-imidazol-2-yl group, a 1H-imidazol-4-yl group, a 1H-pyrazol-1-ylgroup, a 1H-pyrazol-3-yl group, a 1H-pyrazol-4-yl group, a thiophen-2-ylgroup, a thiophen-3-yl group, a furan-2-yl group, a furan-3-yl group, apyrrol-1-yl group, a pyrrol-2-yl group, a pyrrol-3-yl group, anoxazol-2-yl group, an oxazol-4-yl group, an oxazol-5-yl group, anisoxazol-3-yl group, an isoxazol-4-yl group, an isoxazol-5-yl group, athiazol-2-yl group, a thiazol-3-yl group, a thiazol-4-yl group, athiazol-5-yl group, an isothiazol-2-yl group, an isothiazol-4-yl group,an isothiazol-5-yl group, a pyrazol-1-yl group, a pyrazol-3-yl group, apyrazol-4-yl group, a 1,2,3-triazol-1-yl group, a 1,2,3-triazol-4-ylgroup, a 1,2,4-triazol-1-yl group, a 1,2,4-triazol-3-yl group, a1,2,4-triazol-4-yl group, a tetrazol-1-yl group, a tetrazol-5-yl group,a pyridin-2-yl group, a pyridin-3-yl group, a pyridin-4-yl group, apyrazin-2-yl group, a pyrazin-3-yl group, a pyrimidin-2-yl group, apyrimidin-4-yl group, a pyrimidin-5-yl group, a pyrimidin-6-yl group, apyridazin-3-yl group, a pyridazin-4-yl group, an indol-1-yl group, anindol-2-yl group, an indol-3-yl group, an indol-4-yl group, anindol-5-yl group, an indol-6-yl group, an indol-7-yl group, anisoindol-1-yl group, an isoindol-2-yl group, an isoindol-4-yl group, anisoindol-5-yl group, a 1H-pyrrolo[2,3-b]pyridin-1-yl group, a1H-pyrrolo[2,3-b]pyridin-2-yl group, a 1H-pyrrolo[2,3-b]pyridin-3-ylgroup, a 1H-pyrrolo[2,3-b]pyridin-4-yl group, a1H-pyrrolo[2,3-b]pyridin-5-yl group, a 1H-pyrrolo[2,3-b]pyridin-6-ylgroup, a 1H-indazol-1-yl group, a 1H-indazol-3-yl group, a1H-indazol-4-yl group, a 1H-indazol-5-yl group, a 1H-indazol-6-yl group,a 1H-indazol-7-yl group, a methylenedioxyphenyl group, anethylenedioxyphenyl group, a benzofuran-2-yl group, a benzofuran-3-ylgroup, a benzofuran-4-yl group, a benzofuran-5-yl group, abenzofuran-6-yl group, a benzofuran-7-yl group, a2,3-dihydrobenzofuran-2-yl group, a 2,3-dihydrobenzofuran-3-yl group, abenzimidazol-1-yl group, a benzimidazol-2-yl group, a benzimidazol-4-ylgroup, a benzimidazol-5-yl group, a benzoxazol-2-yl group, abenzoxazol-4-yl group, a benzoxazol-5-yl group, a benzothiazol-2-ylgroup, a benzothiazol-4-yl group, a benzothiazol-5-yl group, apurin-2-yl group, a purin-6-yl group, a purin-7-yl group, a purin-8-ylgroup, a quinolin-2-yl group, quinolin-3-yl group, a quinolin-4-ylgroup, quinolin-5-yl group, a quinolin-6-yl group, a quinolin-7-ylgroup, a quinolin-8-yl group, a 5,6,7,8-tetrahydroquinolin-2-yl group, a5,6,7,8-tetrahydroquinolin-3-yl group, a 5,6,7,8-tetrahydroquinolin-4-ylgroup, an isoquinolin-1-yl group, an isoquinolin-3-yl group, anisoquinolin-4-yl group, an isoquinolin-5-yl group, an isoquinolin-6-ylgroup, an isoquinolin-7-yl group, an isoquinolin-8-yl group, aquinazolin-4-yl group, a quinoxalin-2-yl group, a quinoxalin-5-yl group,and a quinoxalin-6-yl group. A 1H-imidazol-1-yl group, a pyrazol-4-ylgroup, a thiophen-3-yl group, a furan-2-yl group, a pyridin-3-yl group,a pyridin-4-yl group, an indol-5-yl group, a1H-pyrrolo[2,3-b]pyridin-5-yl group, a benzofuran-2-yl group, aquinolin-3-yl group, and 5,6,7,8-tetrahydroquinolin-3-yl group arepreferable, a 1H-imidazol-1-yl group, a pyridin-3-yl group, apyridin-4-yl group, an indol-5-yl group, a 1H-pyrrolo[2,3-b]pyridin-5-ylgroup, a benzofuran-2-yl group, a quinolin-3-yl group, and a5,6,7,8-tetrahydroquinolin-3-yl group are more preferable, and a1H-imidazol-1-yl group, a pyridin-3-yl group, and a quinolin-3-yl groupare particularly preferable.

In Formula (I), examples of the “substituent(s)” in the unsaturatedheterocyclic group represented by R¹ include the substituents describedabove. The substituent(s) are preferably 1 to 3 of substituent selectedfrom the group consisting of an alkyl group, an alkoxy group, analkoxy-alkyl group, an aralkyl group, an aralkyloxy-alkyl group, ahalogen atom, a halogenoalkyl group, an acyl group, an optionallysubstituted saturated or unsaturated heterocyclic group, and anoptionally substituted aromatic hydrocarbon group, and more preferably 1to 3 of substituent selected from the group consisting of an alkylgroup; an alkoxy group; an unsaturated heterocyclic group optionallyhaving an alkyl group, a halogenoalkyl group, an aralkyl group, or ahydroxyalkyl group; and an aromatic hydrocarbon group optionally havingan alkyl group, an alkoxy group, or a carbamoyl group. Herein, examplesof the unsaturated heterocyclic group which may be substituted on theunsaturated heterocyclic ring represented by R¹ include pyrazol,imidazol, pyridine, pyrimidine, furan, and thiophene. In addition,examples of the aromatic hydrocarbon group include phenyl and naphthyl.

Specific examples of the “substituent(s)” in the unsaturatedheterocyclic group represented by R¹ can include a methyl group, anethyl group, an n-propyl group, an isopropyl group, an n-butyl group, anisobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group,an ethoxy group, an n-propoxy group, an isopropoxy group, a1-methylpropoxy group, an n-butoxy group, an isobutoxy group, atert-butoxy group, a 1H-pyrazol-4-yl group, a 1-methyl-1H-pyrazol-4-ylgroup, a 1-ethyl-1H-pyrazol-4-yl group, a 1-isopropyl-1H-pyrazol-4-ylgroup, a 1-benzyl-1H-pyrazol-4-yl group, a1-(difluoromethyl)-1H-pyrazol-4-yl group, a1-(hydroxyethyl)-1H-pyrazol-4-yl group, a 1H-imidazol-1-yl group, apyridin-3-yl group, a pyridin-4-yl group, a pyrimidin-5-yl group, afuran-2-yl group, a furan-3-yl group, a thiophen-3-yl group, a phenylgroup, a 4-methoxyphenyl group, a 4-carbamoylphenyl group, a4-isopropylcarbamoylphenyl group, and a 4-dimethylcarbamoylphenyl group.

Specific examples of preferable R¹ include a 1H-imidazol-1-yl group, a4-phenyl-1H-imidazol-1-yl group, a4-(4-carbamoylphenyl)-1H-imidazol-1-yl group, a4-(4-methoxyphenyl)-1H-imidazol-1-yl group, a4-(thiophene-3-yl)-1H-imidazol-1-yl group, a4-(pyridin-3-yl)-1H-imidazol-1-yl group, a4-(pyridin-4-yl)-1H-imidazol-1-yl group, a5-methyl-4-(pyridin-3-yl)-1H-imidazol-1-yl group, a4-(pyrimidin-5-yl)-1H-imidazol-1-yl group, a4-(furan-2-yl)-1H-imidazol-1-yl group, a 4-(furan-3-yl)-1H-imidazol-1-ylgroup, a 4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-ethyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-isopropyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-hydroxymethyl)-(1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-(hydroxyethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-(hydroxymethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-benzyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-(benzyloxyethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a1′H-1,4′-biimidazol-1′-yl group, a pyridin-3-yl group, a pyridin-4-ylgroup, a 5-methoxypyridin-3-yl group, a 6-methoxypyridin-3-yl group, a1-benzyl-1H-pyrazol-4-yl group, a 1-methyl-1H-indol-5-yl group, a1H-pyrrolo[2,3-b]pyridin-5-yl group, a1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, a1-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, a5,6,7,8-tetrahydroquinolin-3-yl group, a quinolin-3-yl group, athiophen-3-yl group, a furan-2-yl group, and a benzofuran-2-yl group. R¹is more preferably a 1H-imidazol-1-yl group, a4-(pyridin-3-yl)-1H-imidazol-1-yl group, a4-(pyridin-4-yl)-1H-imidazol-1-yl group, a4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-ethyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-isopropyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a4-(1-benzyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a quinolin-3-ylgroup, and a 4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl group, andparticularly preferably a 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-ylgroup, a 4-(pyridin-3-yl)-1H-imidazol-1-yl group, and a quinolin-3-ylgroup.

In Formula (I), the “alkyl group having 1 to 6 of carbon atom” in the“optionally substituted alkyl group having 1 to 6 of carbon atom”represented by R² refers to a linear or branched alkyl group having 1 to6 of carbon atom, for example, a methyl group, an ethyl group, ann-propyl group, an isopropyl group, an n-butyl group, an isobutyl group,a sec-butyl group, a tert-butyl group, a pentyl group, or a hexyl group,and is preferably a methyl group, an ethyl group, an n-propyl group, oran isopropyl group.

Examples of the “substituent(s)” in the “optionally substituted alkylgroup having 1 to 6 of carbon atom” represented by R² include thesubstituents described above. Among these, the substituent(s) arepreferably a halogen atom.

The halogen atom-substituted alkyl group is preferably a halogenoalkylgroup having 1 to 6 of carbon atom, and more preferably atrifluoromethyl group.

The “alkenyl group having 2 to 6 of carbon atom” represented by R²refers to the alkenyl group having 2 to 6 of carbon atom describedabove, and is preferably a vinyl group. Examples of the substituent(s)in the alkenyl group include the substituents described above.

R² is more preferably an optionally substituted alkyl group having 1 to6 of carbon atom or an optionally substituted alkenyl group having 2 to6 of carbon atom, even more preferably an alkyl group having 1 to 6 ofcarbon atom which optionally has a halogen atom, or an alkenyl grouphaving 2 to 6 of carbon atom, and particularly preferably an alkyl grouphaving 1 to 4 of carbon atom which optionally has a halogen atom.

Any one or two of Y¹, Y², Y³, and Y⁴ are C—R⁴, and the others are thesame or different and represent CH or N. Among these, preferably, anyone or two of Y¹, Y², Y³, and Y⁴ are C—R⁴, and the others are CH. Morepreferably, Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, andthe others are CH. These preferable aspects are represented by thefollowing formulae:

in the formula, R³ and R⁴ are as defined above.

Among these, (b1) and (b2) are particularly preferable.

In Formula (I), R³ represents a cyano group or —CO—R⁵. Among these,—CO—R⁵ is particularly preferable

In Formula (I), R⁴(s) are the same or different and represent a hydrogenatom, a halogen atom, a cyano group, an optionally substituted alkylgroup having 1 to 6 of carbon atom, a cycloalkyl group having 3 to 7 ofcarbon atom, an alkenyl group having 2 to 6 of carbon atom, an alkoxygroup having 1 to 6 of carbon atom, an aromatic hydrocarbon group,—N(R⁶)(R⁷), —SR⁸, or —CO—R⁹. Among these, R⁴ is preferably a halogenatom, an alkyl group having 1 to 6 of carbon atom which optionally has amono- or di-(C1-C6 alkyl)amino group or a monocyclic 5- to 7-memberedsaturated heterocyclic group having one or two of any heteroatom of N,S, and O, an alkoxy group having 1 to 6 of carbon atom, —N(R⁶)(R⁷),—SR⁸, or —CO—R⁹, and more preferably a halogen atom, an alkyl grouphaving 1 to 6 of carbon atom, or —N(R⁶)(R⁷).

In Formula (I), the “halogen atom” represented by R⁴ refers to thehalogen atom described above and is preferably a chlorine atom.

In Formula (I), the “alkyl group having 1 to 6 of carbon atom” in the“optionally substituted alkyl group having 1 to 6 of carbon atom”represented by R⁴ refers to the alkyl group having 1 to 6 of carbon atomdescribed above and is preferably a methyl group, an ethyl group, ann-propyl group, or an isopropyl group. Examples of the “substituent(s)”in the “optionally substituted alkyl group having 1 to 6 of carbon atom”represented by R⁴ include the substituents described above. The“substituent(s)” are preferably mono- or di-(C1-C6 alkyl)amino groupssuch as an ethylamino group and a dimethylamino group or monocyclic 5-to 7-membered saturated heterocyclic groups having one or two of anyheteroatom of N, S, and O such as a pyrrolidyl group and morpholinogroup.

In Formula (I), the “cycloalkyl group having 3 to 7 of carbon atom”represented by R⁴ refers to the cycloalkyl group having 3 to 7 of carbonatom described above and is preferably a cyclopropyl group.

In Formula (I), the “alkenyl group having 2 to 6 of carbon atom”represented by R⁴ refers to the alkenyl group having 2 to 6 of carbonatom and is preferably a vinyl group or a prop-1-en-2-yl group.

In Formula (I), the “alkoxy group having 1 to 6 of carbon atom”represented by R⁴ refers to the alkoxy group having 1 to 6 of carbonatom described above and is preferably a methoxy group.

In Formula (I), the “mono- or di-alkylamino group” in the “optionallysubstituted mono- or di-alkylamino group” represented by R⁵ refers tothe mono- or dialkylamino group described above, and is preferably amono- or di-(C1-C6 alkyl)amino group. Examples of the “substituent(s)”in the “optionally substituted mono- or di-alkylamino group” representedby R⁵ include the substituents described above.

R⁵ is more preferably an amino group, a hydroxylamino group, or a mono-or di-(C1-C6 alkyl)amino group, and particularly preferably an aminogroup.

In Formula (I), the “alkyl group having 1 to 6 of carbon atom” in the“optionally substituted alkyl group having 1 to 6 of carbon atom”represented by R⁶ or R⁷ refers to the alkyl group having 1 to 6 ofcarbon atom described above, and is preferably an ethyl group, ann-propyl group, an n-butyl group, an isobutyl group, a sec-butyl group,or a pentyl group. Examples of the “substituent(s)” in the “optionallysubstituted alkyl group having 1 to 6 of carbon atom” represented by R⁶or R⁷ include the substituents described above. The “substituent(s)” arepreferably a hydroxyl group, cycloalkyl groups having 3 to 7 of carbonatom (for example, a cyclohexyl group), saturated heterocyclic groups(for example, a pyrrolidyl group and a morpholino group), unsaturatedheterocyclic groups (for example, a pyridyl group), mono- or di-(C1-C6alkyl)amino groups (for example, an ethylamino group and a dimethylaminogroup), (C1-C6 alkyl)thio groups (for example, a methylthio group), oralkoxy groups having 1 to 6 of carbon atom which optionally has ahydroxyl group.

In Formula (I), the “halogenoalkyl group having 1 to 6 of carbon atom”represented by R⁶ or R⁷ refers to the halogenoalkyl group having 1 to 6of carbon atom described above, and is preferably a 2,2-difluoroethylgroup or a 2,2,2-trifluoroethyl group.

In Formula (I), examples of the “cycloalkyl group having 3 to 7 ofcarbon atom” in the “optionally substituted cycloalkyl group having 3 to7 of carbon atom” represented by R⁶ or R⁷ include a cyclopropyl group, acyclobutyl group, a cyclopentyl group, a cyclohexyl group, and acycloheptyl group, and cycloalkyl group having 3 to 7 of carbon atom ispreferably a cyclopropyl group, a cyclopentyl group, or a cyclohexylgroup. Examples of the “substituent(s)” in the “optionally substitutedcycloalkyl group having 3 to 7 of carbon atom” represented by R⁶ or R⁷include the substituents described above. The substituent(s) arepreferably a hydroxyl group, an amino group, an amino acid-derivedacyloxy group, an alkanoylamino group, or an alkylsulfonylamino group.

In Formula (I), the “aralkyl group” in the “optionally substitutedaralkyl group” represented by R⁶ or R⁷ refers to the aralkyl groupdescribed above, and is preferably an aralkyl group having 7 to 12 ofcarbon atom, specifically, a benzyl group. Examples of the“substituent(s)” in the “optionally substituted aralkyl group”represented by R⁶ or R⁷ include the substituents described above.Specific examples of the substituent(s) include saturated heterocyclicgroups such as a pyrrolidinyl group.

In Formula (I), the “aromatic hydrocarbon group” in the “optionallysubstituted aromatic hydrocarbon group” represented by R⁶ or R⁷ refersto the aromatic hydrocarbon group having 6 to 14 of carbon atomdescribed above, and is preferably a phenyl group. Examples of the“substituent(s)” in the “optionally substituted aromatic hydrocarbongroup” represented by R⁶ or R⁷ include the substituents described above.The substituent(s) are preferably halogen atoms, alkylthio groups (forexample, a methylthio group), saturated heterocyclic groups (forexample, a morpholino group), or substituted carbamoyl groups (forexample, a pyrrolidine-carbonyl group).

In the Formula (I), the “saturated heterocyclic group” in the“optionally substituted saturated heterocyclic group” represented by R⁶or R⁷ refers to the saturated heterocyclic group described above, and ispreferably a piperidinyl group or a tetrahydropyranyl group. Examples ofthe “substituent(s)” in the “optionally substituted unsaturatedheterocyclic group” represented by R⁶ or R⁷ include the substituentsdescribed above. The substituent(s) are preferably alkyl groups having 1to 6 of carbon atom (for example, a methyl group), acyl groups (forexample, an acetyl group), carbonyl groups having a saturatedheterocyclic group (for example, a 2,6-dihydroxypyrimidinyl-4-carbonylgroup), or aminoalkylcarbonyl groups (for example, a 2-aminoacetylgroup).

In Formula (I), the “unsaturated heterocyclic group” in the “optionallysubstituted unsaturated heterocyclic group” represented by R⁶ or R⁷refers to the unsaturated heterocyclic group described above, and ispreferably a pyridyl group or an oxazolyl group. Examples of the“substituent(s)” in the “optionally substituted unsaturated heterocyclicgroup” represented by R⁶ or R⁷ include the substituents described above.

In Formula (I), the “saturated heterocyclic group” which is optionallyformed by R⁶ and R⁷ together with the nitrogen atom to which they arebonded refers to a mono- or bi-cyclic saturated heterocyclic grouppreferably having 1 to 4 of any atom of an oxygen atom, a nitrogen atom,and a sulfur atom, and for example, a pyrrolidinyl group, a piperidinylgroup, a piperazinyl group, a hexamethyleneimino group, a morpholinogroup, a thiomorpholino group, a homopiperazinyl group, atetrahydrofuranyl group, or tetrahydropyranyl group.

In Formula (I), it is preferred for the combination of R⁶ and R⁷ that R⁶be a hydrogen atom or an optionally substituted alkyl group having 1 to6 of carbon atom; and R⁷ represent a hydrogen atom, an optionallysubstituted alkyl group having 1 to 6 of carbon atom, an optionallysubstituted cycloalkyl group having 3 to 7 of carbon atom, an optionallysubstituted aralkyl group having 7 to 12 of carbon atom, an optionallysubstituted aromatic hydrocarbon group having 6 to 14 of carbon atom, anoptionally substituted mono- or bi-cyclic saturated heterocyclic grouphaving 1 to 4 of heteroatom selected from the group consisting of N, S,and O, or an optionally substituted mono- or bi-cyclic unsaturatedheterocyclic group having 1 to 4 of heteroatom selected from the groupconsisting of N, S, and O, or R⁶ and R⁷ optionally form a 5- to7-membered saturated heterocyclic group, together with the nitrogen atomto which they are bonded. More preferably, R⁶ is a hydrogen atom, and R⁷is a hydrogen atom, an optionally substituted alkyl group having 1 to 6of carbon atom, an optionally substituted cycloalkyl group having 3 to 7of carbon atom, or an optionally substituted mono- or bi-cyclicsaturated heterocyclic group having 1 to 4 of heteroatom selected fromthe group consisting of N, 8, and O. Particularly preferably, R⁶ is ahydrogen atom, and R⁷ is an optionally substituted alkyl group having 1to 6 of carbon atom or an optionally substituted cycloalkyl group having3 to 7 of carbon atom.

In Formula (I), the “cycloalkyl group having 3 to 7 of carbon atom” inthe “optionally substituted cycloalkyl group having 3 to 7 of carbonatom” represented by R⁸ refers to the cycloalkyl group having 3 to 7 ofcarbon atom described above, and is preferably a cyclohexyl group.Examples of the “substituent(s)” in the “optionally substitutedcycloalkyl group having 3 to 7 of carbon atom” represented by R⁸ includethe substituents described above. The substituent(s) are preferably ahydroxyl group.

In Formula (I), the “aromatic hydrocarbon group” in the “optionallysubstituted aromatic hydrocarbon group” represented by R⁸ refers to thearomatic hydrocarbon group having 6 to 14 of carbon atom describedabove, and is preferably a phenyl group. Examples of the“substituent(s)” in the “optionally substituted aromatic hydrocarbongroup” represented by R⁸ include the substituents described above. Thesubstituent(s) are preferably a hydroxyl group.

R⁸ is preferably an optionally substituted cycloalkyl group having 3 to7 of carbon atom, or an optionally substituted aromatic hydrocarbongroup having 6 to 14 of carbon atom.

In Formula (I), the “mono- or di-alkylamino group” in the “optionallysubstituted mono- or di-alkylamino group” represented by R⁹ refers tothe mono- or dialkylamino group described above, and is preferably amono- or di-(C1-C6 alkyl)amino group. Examples of the “substituent(s)”in the “optionally substituted mono- or di-alkylamino group” representedby R⁹ include the substituents described above.

R⁹ is preferably a hydrogen atom, a hydroxyl group, an amino group or amono- or di-(C1-C6 alkyl)amino group, and particularly preferably ahydrogen atom.

The preferred azabicyclo compound of the invention is a compound ofFormula (I), in which X¹ is CH or N; X² is N and X³ and X⁴ are CH; Y¹and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other isCH; R¹ is any of an optionally substituted 1H-imidazol-1-yl group, anoptionally substituted pyrazol-4-yl group, an optionally substitutedthiophen-3-yl group, an optionally substituted furan-2-yl group, anoptionally substituted pyridin-3-yl group, an optionally substitutedpyridin-4-yl group, an optionally substituted indol-5-yl group, anoptionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, anoptionally substituted benzofuran-2-yl group, an optionally substitutedquinolin-3-yl group, and an optionally substituted5,6,7,8-tetrahydroquinolin-3-yl group; R² is an alkyl group having 1 to6 of carbon atom optionally having a halogen atom or an alkenyl grouphaving 2 to 6 of carbon atom; R³ is —CO—R⁵; R⁴ is a halogen atom, analkyl group having 1 to 6 of carbon atom optionally having a mono- ordi-(C1-C6 alkyl)amino group or a monocyclic 5- to 7-membered saturatedheterocyclic group having one or two of any heteroatom of N, S, and O,an alkoxy group having 1 to 6 of carbon atom, —N(R⁶)(R⁷), —SR⁸, or—CO—R⁹; R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group; R⁶is a hydrogen atom or an optionally substituted alkyl group having 1 to6 of carbon atom; R⁷ is a hydrogen atom, an optionally substituted alkylgroup having 1 to 6 of carbon atom, an optionally substituted cycloalkylgroup having 3 to 7 of carbon atom, an optionally substituted aralkylgroup having 7 to 12 of carbon atom, an optionally substituted aromatichydrocarbon group having 6 to 14 of carbon atom, an optionallysubstituted mono- or bi-cyclic saturated heterocyclic group having 1 to4 of heteroatom selected from the group consisting of N, S, and O, or anoptionally substituted mono- or bi-cyclic unsaturated heterocyclic grouphaving 1 to 4 of heteroatom selected from the group consisting of N, S,and O, or R⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic grouptogether with a nitrogen atom to which they are bonded; R⁸ is anoptionally substituted cycloalkyl group having 3 to 7 of carbon atom oran optionally substituted aromatic hydrocarbon group having 6 to 14 ofcarbon atom; and R⁹ is a hydrogen atom, a hydroxyl group, an aminogroup, or a mono- or di-(C1-C6 alkyl)amino group.

More specifically, the azabicyclo compound is3-ethyl-4-({3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (hereinafter, referred to as Compound 1).

The salt of the azabicyclo compound of the invention is not particularlylimited as long as it is a pharmaceutically acceptable salt, andexamples thereof include acid addition salts of inorganic acids (forexample, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, nitric acid, and phosphoric acid) and organic acids (for example,formic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonicacid, p-toluenesulfonic acid, and glutamic acid); salts of inorganicbases (for example, sodium, potassium, magnesium, calcium, andaluminum), organic bases (for example, methylamine, ethylamine,meglumine, and ethanolamine), or a basic amino acids (for example,lysine, arginine, and ornithine); and ammonium salts.

Incidentally, the azabicyclo compound of the invention or a salt thereofcan be synthesized according to the method described in WO 2011/004610A, for example.

As described in Examples below, when the azabicyclo compound of theinvention or a salt thereof is administered in combination withextremely various ranges of antitumor agents having different actionmechanisms, the antitumor effect is synergistically potentiated. The“other antitumor agent” described in the invention is not particularlylimited as long as it is a pharmaceutical having antitumor activity, andas the form thereof, any of a low molecular compound, an antibody, and anucleic acid may be employed. Specific examples of antitumor agentsexhibiting the synergic effect with the azabicyclo compound of theinvention or a salt thereof include antitumor antibiotic substances suchas amrubicin, doxorubicin, doxyl, epirubicin, and mitomycin C;alkylating agents such as cyclophosphamide and nimustine; platinum-basedagents such as cisplatin, carboplatin, and oxaliplatin; pyrimidine-basedantimetabolite agents such as 5-fluorouracil (5-FU),tegafur/gimeracil/oteracil potassium (TS-1, generic name“tegafur/gimeracil/oteracil potassium compounding agent” (trade name:“TS-1”)), tegafur/uracil (UFT, generic name “tegafur/uracil compoundingagent” (trade name: “UFT”)), capecitabine, doxifluridine,5-fluoro-2′-deoxyuridine (FdUrd), gemcitabine, and cytarabine;purine-based antimetabolite agents such as fludarabine, bendamustine,cladribine, and nelarabine; folic acid antimetabolite agents such aspemetrexed and methotrexate; plant alkaloid-based antitumor agents suchas paclitaxel (for example, TAXOL or ABRAXANE), docetaxel, irinotecan,and etoposide; immunomodulating drugs such as lenalidomide; lowmolecular weight molecular targeted drugs such as imatinib, gefitinib,dasatinib, erlotinib, lapatinib, everolimus, temsirolimus, bortezomib,crizotinib, vemurafenib, and ZD6244; and antibody molecular targeteddrugs such as bevacizumab, trastuzumab, cetuximab, and rituximab. Amongthese, in terms of the synergic effect of antitumor effect in the caseof concurrently using the azabicyclo compound of the invention or a saltthereof, one or more of agent selected from the group consisting ofantitumor antibiotic substances, platinum-based agents, pyrimidine-basedantimetabolite agents, purine-based antimetabolite agents, folic acidantimetabolite agents, plant alkaloid-based antitumor agents,immunomodulating drugs, and low molecular weight molecular targeteddrugs are preferable.

As a specific antitumor agent, in terms of the synergic effect ofantitumor effect in the case of concurrently using the azabicyclocompound of the invention or a salt thereof, one or more of kind(s)selected from the group consisting of amrubicin, doxorubicin, mitomycinC, cisplatin, oxaliplatin, 5-FU, TS-1, UFT, gemcitabine, cytarabine,pemetrexed, paclitaxel (for example, TAXOL or ABRAXANE), docetaxel,irinotecan, etoposide, lenalidomide, imatinib, gefitinib, dasatinib,erlotinib, lapatinib, bortezomib, crizotinib, vemurafenib, and ZD6244are preferable, one or more of kind(s) selected from the groupconsisting of amrubicin, doxorubicin, cisplatin, oxaliplatin,gemcitabine, cytarabine, pemetrexed, paclitaxel (for example, TAXOL orABRAXANE), docetaxel, etoposide, lenalidomide, imatinib, gefitinib,dasatinib, erlotinib, lapatinib, and crizotinib are more preferable, andone or more of kind(s) selected from the group consisting of amrubicin,cisplatin, etoposide, gemcitabine, paclitaxel (for example, TAXOL orABRAXANE), docetaxel, and crizotinib are particularly preferable.

Specific examples of a cancer to be treated by the antitumor agent ofthe invention include head and neck cancer, digestive organ cancer (forexample, esophageal cancer, stomach cancer, duodenal cancer, livercancer, biliary tract cancer (for example, gallbladder/bile ductcancer), pancreatic cancer, small intestinal cancer, large intestinecancer (for example, colorectal cancer, colon cancer, or rectal cancer),lung cancer (for example, non-small cell lung cancer or small cell lungcancer), breast cancer, ovarian cancer, uterus cancer (for example,cervical cancer or uterine corpus cancer), kidney cancer, bladdercancer, prostate cancer, skin cancer (for example, malignant melanoma orepidermal cancer), and blood cancer (for example, multiple myeloma oracute myelocytic leukemia). Among these, in terms of the synergic effectof the antitumor effect when the azabicyclo compound of the invention ora salt thereof is used in combination with the antitumor agent, thecancer is preferably digestive organ cancer, lung cancer, breast cancer,skin cancer, or blood cancer, and more preferably colorectal cancer,lung cancer, breast cancer, gallbladder cancer, pancreatic cancer,stomach cancer, skin cancer, or blood cancer. Incidentally, herein, thecancer includes not only primary tumor but also cancer metastasizing toother organ(s) (for example, liver). In addition, the antitumor agent ofthe invention may be used for postoperative adjuvant chemotherapy whichis performed for prevention of recurrence after a tumor is removedsurgically or may be used for preoperative adjuvant chemotherapy whichis preliminarily performed for removing surgically a tumor.

There is no particular limitation on the administration form of theantitumor agent of the invention, and appropriate form can be selectedin accordance with the therapeutic purpose. Specific examples of theform of the antitumor agent include oral agents (for examples, tablets,coated tablets, powder, granules, capsules, and liquid), injections,suppositories, cataplasms, and ointments.

The administration schedule of the antitumor agent of the invention isappropriately selected in the range in which each active ingredientexerts the antitumor effect, and each active ingredient is administeredsimultaneously or separately at an interval.

The antitumor agent of the invention may be prepared in such a mannerthat respective active ingredients are separated into multiple dosageforms or are collectively prepared in one dosage form, on the basis ofthe administration forms or the administration schedules of the activeingredients. In addition, each drug formulation may be produced and soldin one package suitable for use at each event of combined administrationor may be produced and sold in separate packages.

The antitumor agent in the invention can be prepared through a generallyknown method by use of a pharmacologically acceptable carrier, accordingto the administration form. Such a carrier can be selected from thegroup consisting of a variety of carriers generally employed inpharmaceuticals, and examples thereof can include an excipient, abinder, a disintegrant, a lubricant, a diluent, a solubilizing agent, asuspending agent, a tonicity agent, a pH-adjusting agent, a buffer, astabilizer, a coloring agent, a flavoring agent, and a deodorant.

The invention also relates to an antitumor effect potentiator containingthe azabicyclo compound of the invention or a salt thereof, which isused for potentiating the antitumor effect of other antitumor agent(s)with respect to a cancer patient. The antitumor effect potentiator hasthe formulation aspect of the antitumor agent described above.

The invention also relates to an antitumor agent containing theazabicyclo compound of the invention or a salt thereof, which is usedfor treating a cancer patient who has been administered other antitumoragent(s). The antitumor agent has the above-described formulationaspect.

The invention also relates to a kit preparation including directions foruse in which the azabicyclo compound of the invention or a salt thereofand administration of the azabicyclo compound of the invention or a saltthereof in combination with other antitumor agent(s) to a cancer patientare described. Herein, the “directions for use” may be directions foruse in which the above-described dosage is described. Although it doesnot matter whether the directions for use are legally bound or not,directions for use in which the above-described dosage is recommendedare preferable. Specifically, a package insert or a pamphlet isexemplified. In addition, the kit preparation including directions foruse may be a kit preparation in which directions for use are printed onor attached to the package of the kit preparation or a kit preparationin which directions for use are enclosed in the package of the kitpreparation together with an antitumor agent.

EXAMPLES

Hereinafter, the invention will be described in more detail by means ofExamples and Reference Examples.

Example 1

A combination of Compound 1 and docetaxel exhibits the potentiatedantitumor activity with respect to a human tumor cell of nude mousexenograft model having a non-small cell lung cancer (NSCLC) cellNCI-H2170.

NCI-H2170 (ATCC #CRL-5928) as a human non-small cell lung cancer (NSCLC)cell line was obtained from American Type Culture Collection (ATCC;Manassas, Va., USA). In RPMI-1640 (containing 4.5 g/L of glucose, 10 mMof HEPES, and 1 mM of sodium pyruvate) (Wako Pure Chemical Industries,Ltd.) medium supplemented with 10% fetal bovine serum (FBS), cell lineswere cultured. The cells cryopreserved in liquid nitrogen were quicklythawed at 37° C., transferred to a tissue culture flask containing amedium, and allowed to grow in a 5% CO₂ incubator at 37° C. TheNCI-H2170 cell lines were sub-cultured once to twice a week at adilution ratio of 1:5 to 1:10. The cells which were grown to 80 to 90%confluence in a 75 cm² flask were washed with 10 mL of phosphate buffersaline (PBS), and 10 mL of 0.25% trypsin-EDTA was then added thereto,followed by incubation until the cells were separated from the surfaceof the flask. 10 mL of medium for inactivation of trypsin was addedthereto, a cell suspension was collected, and after centrifugalseparation, the cell pellet was re-suspended in 10 mL of growth mediumand then seeded in a 175 cm² flask into which 30 mL of medium was put,followed by incubation in a 5% CO₂ incubator at 37° C. When the flaskreached 80 to 90% confluence, the above-described sub-culturing wasrepeated until cells sufficient for transplantation into mice wereobtained.

Five-week old BALB/cAJcl-nu/nu mice (nude mice) were obtained from CREAJapan, Inc. Animals were housed in 5 or 6 microisolator cages under a12-hour light/12-hour dark cycle, acclimated at least one week beforeuse, and appropriately fed with a usual feed. The animals at the time oftransplantation were six- to eight-week old. In order to transplantNCI-H2170 cells to the nude mice, cells were collected as describedabove, washed in PBS, and re-suspended at a concentration of 5×10⁷cell/mL in 50% PBS and 50% Matrigel basement membrane matrix (#356237;BD Biosciences; Bedford, Mass., USA). A 5×10⁶ cell/0.1 mL of cellsuspension was transplanted subcutaneously to the right dorsal region ofthe nude mouse by using a 1 mL tuberculin syringe and a 25 G needle.

Subsequently, the cell was allowed to grow for one to two weeks aftertransplantation until the tumor volume (TV) reached 100 to 300 mm³.Digimatic Caliper was used in measurement of the tumor diameter, themajor axis and the minor axis of the tumor were measured, and TV wascalculated by the following formula.TV (mm³)=(Major axis×minor axis²)/2, units of the major axis and theminor axis: mm

Animals having an extremely small or large tumor volume were excludedand the remaining animals were allocated to each group by a stratifiedrandomization allocation method using TV as an index. A relative tumorvolume (RTV) was calculated from TV as an endpoint. In addition, atreatment/control (T/C) value (%) that is an RTV ratio of the RTV of thepharmaceutical administered group to the RTV of the control group on theend date of test period was calculated as an evaluation index. RTV andT/C (%) were calculated by the following formula.RTV=TV_(n)/TV₁T/C (%)=(Average RTV of each pharmaceutical administered group on testend date)/(Average RTV of control group on test end date)×100

TV₁ represents the tumor volume of Day 1.

In order to administer Compound 1, a 0.5% hypromellose aqueous solutionwas prepared. Hypromellose was weighed in a beaker, and distilled water(Otsuka Pharmaceutical Factory, Inc.) was added thereto in an amount ofabout 80% of the preparation amount. The mixture was completelydissolved by being stirred overnight using a stirrer at alow-temperature chamber, the resultant solution was transferred to ameasuring cylinder, and distilled water was added to dilute to thepreparation amount. Compound 1 was weighed in a necessary amount,pulverized with an agate mortar, suspended with a 0.5% hypromelloseaqueous solution to have a predetermined concentration, and thensubjected to ultrasonic treatment, thereby obtaining a homogeneoussuspension. 10 mL of this suspension was administered orally per kg ofbody weight. Incidentally, the suspension was stored in a refrigeratorat times other than administration. This suspension isrefrigerator-stable for two weeks.

As docetaxel, 80 mg of Taxotere (registered trademark) for intravenousdrip infusion (Sanofi-Aventis SA) was dissolved according to the packageinsert, and was diluted with physiological saline so as to have apredetermined concentration immediately before administration. On thefirst day of administration, 5 mL of the prepared docetaxel wasadministered intravenously per kg of body weight.

Both the treatment with 5 mg/kg of body weight of Compound 1 and thetreatment with 15 mg/kg of body weight of docetaxel slightly inhibitedthe growth of NCI-H2170 tumor in the nude mice, and the T/C values were72 and 86, respectively. In contrast, the concomitant treatment with acombination of 5 mg/kg of body weight of Compound 1 and 15 mg/kg of bodyweight of docetaxel further inhibited the growth of NCI-H2170 tumor inthe nude mice, and the T/C value was 43. Further, the treatment with oneof 10 mg/kg of body weight of Compound 1 and 30 mg/kg of body weight ofdocetaxel or a combination thereof were carried out. However, the effectobserved in each concomitant treatment group was potentiated moresignificantly (P<0.05; Intersection-Union test) compared to the effectobserved in the group treated only with any one of pharmaceuticals. Theresults thereof are shown in FIG. 1. Regarding the average body weightchange on the end date of test period, all of the groups treated withthe combination of Compound 1 and docetaxel were accompanied with notoxicity with respect to the control group.

Example 2

A combination of Compound 1 and paclitaxel exhibits the potentiatedantitumor activity with respect to a human tumor cell of nude mousexenograft model having NSCLC NCI-H441 cells.

An NCI-H441 cell (ATCC #HTB-174) was transplanted to nude mice accordingto the description in Example 1. The cell was allowed to grow for oneweek after transplantation until the large majority of tumors reached100 to 300 mm³.

In order to administer paclitaxel, paclitaxel was weighed in a necessaryamount, ethanol (NACALAI TESQUE, INC.) was added thereto in an amount of10% of the preparation amount, and the mixture was dissolved byultrasonic treatment. Next, Cremophor EL (NACALAI TESQUE, INC.) wasadded thereto in the same amount as ethanol, and the mixture wasdissolved by ultrasonic treatment. Physiological saline was added andmixed in an amount of 10% of the preparation amount immediately beforeadministration, thereby preparing a paclitaxel administration solution.On the first day of administration, 5 mL of the paclitaxeladministration solution was administered intravenously per kg of bodyweight.

As shown in FIG. 2, both the treatment with 5 mg/kg of body weight ofCompound 1 and the treatment with 30 mg/kg of body weight of paclitaxelinhibited the growth of NCI-H441 tumor in the nude mice, and the T/Cvalues were 63 and 41, respectively. In contrast, in the case ofconcomitant treatment with these pharmaceuticals, the inhibitory effectof NCI-H441 tumor growth in the nude mice was potentiated and the T/Cvalue was 28. Further, the treatment with 15 mg/kg of body weight or 60mg/kg of body weight of docetaxel alone and the concomitant treatmentwith docetaxel and 5 mg/kg of body weight of Compound 1 were carriedout. However, the effect observed in each concomitant treatment groupwas potentiated more significantly (P<0.05; Intersection-Union test)compared to the effect observed in the group treated only with any oneof pharmaceuticals. Regarding the toxicity using the body weight changeon the end date of test period as an index, the group treated with thecombination of Compound 1 and paclitaxel was well in the tolerable rangewith respect to the control group. In addition, the same result was alsoobtained in the stomach cancer line.

Example 3

A combination of Compound 1 and cisplatin exhibits the potentiatedantitumor activity with respect to a human tumor cell of nude mousexenograft model having a stomach cancer line NCI-N87 cell.

An NCI-N87 cell (ATCC #CRL-5822) was transplanted to nude mice accordingto the description in Example 1. The cell was allowed to grow for oneweek after transplantation until the large majority of tumors reached100 to 300 mm³.

As cisplatin, 25 mg of Briplatin for injection (Bristol-Myers SquibbCompany) was dissolved according to the package insert, and was dilutedwith physiological saline so as to have a predetermined concentrationimmediately before administration. On the first day of administration,14.0 mL of the prepared cisplatin was administered intravenously per kgof body weight.

As shown in FIG. 3, both the treatment with 5 mg/kg of body weight ofCompound 1 and the treatment with 7 mg/kg of body weight of cisplatininhibited the growth of NCI-N87 tumor in the nude mice, and the T/Cvalues were 51 and 65, respectively. In contrast, in the case ofconcomitant treatment with these pharmaceuticals, the inhibitory effectof NCI-N87 tumor growth in the nude mice was potentiated and the T/Cvalue was 26. Further, the treatment with 10 mg/kg of body weight or 20mg/kg of body weight of Compound 1 alone and the concomitant treatmentwith Compound 1 and 7 mg/kg of body weight of cisplatin were carriedout. However, the effect observed in each concomitant treatment groupwas potentiated more significantly (P<0.05; Intersection-Union test)compared to the effect observed in the group treated only with any oneof pharmaceuticals. Regarding the toxicity using the body weight changeon the end date of test period as an index, the group treated with thecombination of Compound 1 and cisplatin was well in the tolerable rangewith respect to the control group.

Example 4

A combination of Compound 1 and amrubicin exhibits the potentiatedantitumor activity with respect to a human tumor cell of nude mousexenograft model having a small cell lung cancer line SBC-1 cell.

An SBC-1 cell (purchased from Health Science Research Resources Bank,#JCRB0816) was transplanted to nude mice according to the description inExample 1. The cell was allowed to grow for one week aftertransplantation until the large majority of tumors reached 100 to 300mm³.

As amrubicin, 20 mg of Calsed (registered trademark) for injection(Sumitomo Dainippon Pharma Co., Ltd.) was dissolved according to thepackage insert, and was diluted with physiological saline so as to havea predetermined concentration immediately before administration. On thefirst day of administration, 10.0 mL of the prepared amrubicin wasadministered intravenously per kg of body weight.

On Days 1, 3, 5, 8, 10, and 12, 10.0 mL of Compound 1 was administeredorally per kg of body weight.

As shown in FIG. 4, both the treatment with 28 mg/kg of body weight ofCompound 1 and the treatment with 12.5 mg/kg of body weight of amrubicininhibited the growth of SBC-1 tumor in the nude mice, and the T/C valueswere 49 and 40, respectively. In contrast, in the case of concomitanttreatment with these pharmaceuticals, the inhibitory effect of SBC-1tumor growth in the nude mice was potentiated and the T/C value was 17.Further, the treatment with 20 mg/kg of body weight of Compound 1 aloneand the concomitant treatment with Compound 1 and 12.5 mg/kg of bodyweight of amrubicin were carried out. However, the effect observed ineach concomitant treatment group was potentiated more significantly(P<0.05; Intersection-Union test) compared to the effect observed in thegroup treated only with any one of pharmaceuticals. Regarding thetoxicity using the body weight change on the end date of test period asan index, the group treated with the combination of Compound 1 andamrubicin was well in the tolerable range with respect to the controlgroup.

Example 5 In Vitro Combination Analysis of Compound 1 and Crizotinib

A. Material and Method

In RPMI-1640 medium (Wako Pure Chemical Industries, Ltd.) supplementedwith 10% fetal bovine serum (Thermo Scientific), human stomach cancercell lines NUGC-4 and MKN45 (Health Science Research Resources Bank,HSRRB) were allowed to grow. All of the cells were maintained at 37° C.and 5% CO₂, and sub-cultured once to twice a week at a dilution ratio of1:5 to 1:20.

Cell Survival Assay

The cell survival rate was measured using CellTiter-Glo. The cells wererecovered by a general method, suspended in RPMI-1640 mediumsupplemented with 10% fetal bovine serum and antibiotic substances(penicillin and streptomycin), and seeded in a 384-well plate. Thenumber of cells to be seeded was set to 500 cell/20 μL per well. Theseeded cells were incubated at 37° C. and 5% CO₂ for 24 hours, and then5 μL of a medium supplemented with crizotinib and Compound 1 or Vehicle(DMSO) was added thereto. As crizotinib, nine of a 3-fold dilutionseries from 10 μM and zero concentration (DMSO) were used, and asCompound 1, seven of 3-fold dilution series from 10 μM and zeroconcentration (DMSO) were used. All of 80 combinations thereof wereexamined. With respect to each combination, four wells were allocated.Further, incubation was carried out at 37° C. and 5% CO₂ for 72 hours.25 μL of CellTiter-Glo liquid per well was added, and then incubationwas carried out at room temperature for 10 minutes. Thechemiluminescence was measured by Envision as a plate reader. Theaverage value of four wells of each combination was calculated from theobtained data, and the standardized cell survival rate was calculatedwith respect to the control added with a medium supplemented withVehicle. The Fa (Fraction of Affect) was calculated by subtracting thecell survival rate from 1.

The half inhibition concentration (IC50) of each pharmaceutical wasdetermined using median effect analysis software CalcuSyn 2.0 (CalcuSyn,Inc.). Subsequently, the combination index (CI) of each combinationconcentration of pharmaceuticals was determined. The CI values of morethan 1, equal to 1, and less than 1 each indicate antagonistic effect,additive effect, and synergic effect (Table 1) (Pharmacol Rev. 2006;58(3):621-81, BMC Complement Altern Med. 2013; 13:212, Anticancer Res.2005; 25(3B):1909-17).

TABLE 1 (Explanation of combination index value) Range of CI (upperlimit) Explanation 0.1 Extremely strong synergic effect 0.3 Strongsynergic effect 0.7 Synergic effect 0.85 Moderate synergic effect 0.9Slight synergic effect 1 Substantially additive 1.2 Modest antagonisticeffect 1.45 Moderate antagonistic effect 3.3 Antagonistic effect 10Strong antagonistic effect >10 Extremely strong antagonistic effect

Further, the Fa value close to 1 is considered to be a concentrationrange in which the effect of one of pharmaceuticals is too strong, andthe Fa value close to 0 is considered to be a concentration range inwhich the effect of one of pharmaceuticals is too weak. These values arenot suitable for discussion on the synergistic effect. Therefore, theconcentration combination of both the pharmaceuticals satisfying0.2≦Fa≦0.8 was extracted from the Fa values calculated by 80concentration combinations of Compound 1 and crizotinib in total in theNUGC-4 cell, and the extracted concentration combination is used in thelinear curve fitting by CalcuSyn to obtain a CI.

B. Result

The obtained CI and the concentrations of both pharmaceuticals appliedtherewith were examined and the concentration range of each of both thepharmaceuticals in which the CI became moderate degree or highersynergic effect (less than 0.85) was found (Table 2).

TABLE 2 Com- pound 1 Crizotinib Concomitant (nM) (nM) Fa CI ratio13.7174 4.57247 0.34 0.291 Strong 1:0.33333 synergic effect 13.717413.7174 0.527 0.139 Strong 1:1     synergic effect 13.7174 41.1523 0.530.383 Synergic effect 1:3.00001 41.1523 4.57247 0.339 0.368 Synergiceffect 1:0.11111 41.1523 13.7174 0.579 0.103 Strong 1:0.33333 synergiceffect 41.1523 41.1523 0.534 0.391 Synergic effect 1:1     41.1523123.457 0.567 0.816 Moderate 1:3     synergic effect 123.457 1.524160.289 0.622 Synergic effect 1:0.01235 123.457 4.57247 0.417 0.319Synergic effect 1:0.03704 123.457 13.7174 0.581 0.149 Strong 1:0.11111synergic effect 123.457 41.1523 0.582 0.3 Synergic effect 1:0.33333370.37 1.52416 0.645 0.148 Strong 1:0.00412 synergic effect 370.374.57247 0.624 0.182 Strong 1:0.01235 synergic effect 370.37 13.71740.631 0.205 Strong 1:0.03704 synergic effect 370.37 41.1523 0.64 0.278Strong 1:0.11111 synergic effect 370.37 123.457 0.66 0.446 Synergiceffect 1:0.33333 1111.11 1.52416 0.75 0.201 Strong 1:0.00137 synergiceffect 1111.11 4.57247 0.74 0.221 Strong 1:0.00412 synergic effect1111.11 13.7174 0.742 0.227 Strong 1:0.01235 synergic effect 1111.1141.1523 0.739 0.262 Strong 1:0.03704 synergic effect 1111.11 123.4570.722 0.41 Synergic effect 1:0.11111 3333.33 41.1523 0.717 0.833Moderate 1:0.01235 synergic effect

In the concentration range from 13.7174 nM to 1111.11 nM of Compound 1and the concentration range from 4.57247 nM to 41.1523 nM of crizotinibin the NUGC-4 cell, a large number of combinations exhibiting a strongsynergic effect were found. This means that in these concentrationranges, cell death was induced greater than expected from the additiveeffect of dosage of respective pharmaceuticals.

In addition, similarly to the result of the NUGC-4 cell described above,regarding the MKN45 cell, when the incubation was carried out for 72hours while Compound 1 and crizotinib were simultaneously added, a largenumber of combinations exhibiting a strong synergic effect also werefound in the concentration range from 13.7174 nM to 370.37 nM ofCompound 1 and the concentration range from 13.7174 nM to 123.457 nM ofcrizotinib (Table 3).

TABLE 3 Com- pound 1 Crizotinib Concomitant (nM) (nM) Fa CI ratio13.7174 41.1523 0.796 0.048 Extremely strong 1:3.00001 synergic effect13.7174 370.37 0.795 0.418 Synergic effect  1:27.00001 41.1523 13.71740.346 0.772 Moderate 1:0.33333 synergic effect 41.1523 41.1523 0.7920.056 Extremely strong 1:1     synergic effect 123.457 13.7174 0.3950.709 Moderate 1:0.11111 synergic effect 370.37 1.52416 0.562 0.34Synergic effect 1:0.00412 370.37 4.57247 0.562 0.367 Synergic effect1:0.01235 370.37 13.7174 0.727 0.153 Strong 1:0.03704 synergic effect370.37 41.1523 0.792 0.123 Strong  1: 0.11111 synergic effect 370.37123.457 0.796 0.21 Strong 1:0.33333 synergic effect 370.37 370.37 0.780.575 Synergic effect 1:1     1111.11 1.52416 0.733 0.354 Synergiceffect 1:0.00137 1111.11 4.57247 0.74 0.344 Synergic effect 1:0.004121111.11 13.7174 0.723 0.408 Synergic effect 1:0.01235 1111.11 41.15230.769 0.332 Synergic effect 1:0.03704 1111.11 123.457 0.753 0.523Synergic effect 1:0.11111 3333.33 1.52416 0.764 0.846 Moderate 1:0.00046synergic effect 3333.33 4.57247 0.77 0.813 Moderate 1:0.00137 synergiceffect 3333.33 41.1523 0.776 0.827 Moderate 1:0.01235 synergic effect

Example 6 In Vitro Combination Analysis of Compound 1 and OtherAntitumor Agents

The same in vitro combination analysis was also performed on acombination of Compound 1 and other antitumor agents with respect to acell line other than those described above. All of the antitumor agentspresented in Table 4 to Table 39 exhibited moderate degree or highersynergic effect with Compound 1 (CI<0.85). Particularly, in imatinib,etoposide, erlotinib, oxaliplatin, gefitinib, gemcitabine, cisplatin,cytarabine, dasatinib, doxorubicin, docetaxel, paclitaxel, pemetrexed,lapatinib, and lenalidomide, a strong synergic effect (CI<0.30)exhibited in one or more of concentration combination.

TABLE 4 <Antitumor agent: 5-FU, Cancer type: epidermal cancer, Cellline: A431> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) Fa CICI_COMMENT ratio 13.7174 5555.56 0.563 0.475 Synergic effect 1:405.00095 41.1523 5555.56 0.537 0.613 Synergic effect  1:134.999993333.33 7.62079 0.676 0.804 Moderate 1:0.00229 synergic effect 3333.3322.8624 0.678 0.797 Moderate 1:0.00686 synergic effect 3333.33 68.58710.698 0.726 Moderate 1:0.02058 synergic effect 3333.33 205.761 0.6880.765 Moderate 1:0.06173 synergic effect 3333.33 617.284 0.701 0.728Moderate 1:0.18519 synergic effect 3333.33 1851.85 0.716 0.698 Synergiceffect 1:0.55556 3333.33 5555.56 0.712 0.786 Moderate 1:1.66667 synergiceffect

TABLE 5 <Antitumor agent: ZD6244, Cancer type: malignant melanoma, Cellline: A375> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) Fa CICI_COMMENT ratio 13.7174 41.1523 0.252 0.55 Synergic effect 1:3.0000113.7174 123.457 0.479 0.314 Synergic effect 1:9.00003 13.7174 370.370.59 0.442 Synergic effect  1:27.00001 13.7174 1111.11 0.68 0.692Synergic effect  1:81.00004 41.1523 123.457 0.447 0.415 Synergic effect1:3     41.1523 370.37 0.577 0.501 Synergic effect 1:8.99998 41.15231111.11 0.685 0.679 Synergic effect  1:26.99995 123.457 123.457 0.4320.546 Synergic effect 1:1     123.457 370.37 0.572 0.576 Synergic effect1:2.99999 123.457 1111.11 0.681 0.741 Moderate 1:8.99998 synergic effect370.37 41.1523 0.352 0.758 Moderate 1:0.11111 synergic effect 370.37123.457 0.443 0.772 Moderate 1:0.33333 synergic effect 370.37 370.370.606 0.624 Synergic effect 1:1     370.37 1111.11 0.69 0.813 Moderate1:3     synergic effect 1111.11 41.1523 0.61 0.741 Moderate 1:0.03704synergic effect 1111.11 123.457 0.68 0.63 Synergic effect 1:0.111111111.11 370.37 0.753 0.547 Synergic effect 1:0.33333 1111.11 1111.110.769 0.722 Moderate 1:1     synergic effect

TABLE 6 <Antitumor agent: SN-38, Cancer type: epidermal cancer, Cellline: A431> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) Fa CICI_COMMENT ratio 13.7174 13.7174 0.584 0.437 Synergic effect 1:1    41.1523 13.7174 0.514 0.652 Synergic effect 1:0.33333 41.1523 41.15230.773 0.384 Synergic effect 1:1     123.457 41.1523 0.719 0.578 Synergiceffect 1:0.33333 3333.33 1.52416 0.557 0.584 Synergic effect 1:0.000463333.33 4.57247 0.558 0.694 Synergic effect 1:0.00137 3333.33 13.71740.611 0.807 Moderate 1:0.00412 synergic effect 3333.33 41.1523 0.7850.556 Synergic effect 1:0.01235

TABLE 7 <Antitumor agent: imatinib, Cancer type: acute myelocyticleukemia, Cell line: Kasumi-1> Anti- Com- tumor pound agent Concomitant1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 370.37 0.327 0.566 Synergiceffect  1:27.00001 13.7174 1111.11 0.488 0.272 Strong  1:81.00004synergic effect 13.7174 3333.33 0.51 0.595 Synergic effect  1:243.0001341.1523 370.37 0.369 0.446 Synergic effect 1:8.99998 41.1523 1111.110.52 0.256 Strong  1:26.99995 synergic effect 41.1523 3333.33 0.55 0.443Synergic effect  1:80.99985 123.457 370.37 0.409 0.561 Synergic effect1:2.99999 123.457 1111.11 0.564 0.335 Synergic effect 1:8.99998 123.4573333.33 0.556 0.576 Synergic effect  1:26.99993 370.37 4.57247 0.6160.592 Synergic effect 1:0.01235 370.37 13.7174 0.621 0.583 Synergiceffect 1:0.03704 370.37 41.1523 0.576 0.673 Synergic effect 1:0.11111370.37 123.457 0.599 0.631 Synergic effect 1:0.33333 370.37 370.37 0.6320.578 Synergic effect 1:1     370.37 1111.11 0.694 0.48 Synergic effect1:3     370.37 3333.33 0.697 0.516 Synergic effect 1:9     370.37 300000.737 0.722 Moderate  1:81.00008 synergic effect

TABLE 8 <Antitumor agent: etoposide, Cancer type: large intestinecancer, Cell line: HCT-116> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 13.7174 1111.11 0.421 0.772 Moderate 1:81.00004 synergic effect 41.1523 3333.33 0.638 0.741 Moderate 1:80.99985 synergic effect 123.457 1111.11 0.495 0.638 Synergic effect1:8.99998 123.457 3333.33 0.655 0.723 Moderate  1:26.99993 synergiceffect 370.37 3333.33 0.71 0.648 Synergic effect 1:9     1111.11 1.524160.637 0.716 Moderate 1:0.00137 synergic effect 1111.11 4.57247 0.640.709 Moderate 1:0.00412 synergic effect 1111.11 13.7174 0.623 0.754Moderate 1:0.01235 synergic effect 1111.11 41.1523 0.638 0.722 Moderate1:0.03704 synergic effect 1111.11 123.457 0.671 0.655 Synergic effect1:0.11111 1111.11 370.37 0.685 0.662 Synergic effect 1:0.33333 1111.111111.11 0.714 0.689 Synergic effect 1:1     1111.11 3333.33 0.753 0.808Moderate 1:3     synergic effect

TABLE 9 <Antitumor agent: etoposide, Cancer type: epidermal cancer, Cellline: A431> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) Fa CICI_COMMENT ratio 13.7174 3333.33 0.279 0.29 Strong  1:243.00013 synergiceffect 13.7174 10000 0.624 0.037 Extremely strong  1:729.00112 synergiceffect 41.1523 10000 0.672 0.028 Extremely strong  1:242.99978 synergiceffect 123.457 3333.33 0.23 0.649 Synergic effect 1:26.99993 123.45710000 0.616 0.061 Extremely strong 1:80.99986 synergic effect 370.3710000 0.587 0.132 Strong 1:27.00003 synergic effect 1111.11 10000 0.4720.555 Synergic effect 1:9.00001  10000 3333.33 0.782 0.79 Moderate1:0.33333  synergic effect 10000 10000 0.783 0.789 Moderate 1:1    synergic effect

TABLE 10 <Antitumor agent: erlotinib, Cancer type: non- small cell lungcancer, Cell line: A549> Anti- Com- tumor pound agent Concomitant 1 (nM)(nM) Fa CI CI_COMMENT ratio 13.7174 370.37 0.275 0.572 Synergic effect 1:27 13.7174 1111.11 0.377 0.715 Moderate  1:81 synergic effect 13.717410000 0.695 0.611 Synergic effect  1:729 41.1523 123.457 0.275 0.36Synergic effect 1:3 41.1523 370.37 0.345 0.426 Synergic effect 1:941.1523 1111.11 0.386 0.749 Moderate  1:27 synergic effect 41.15233333.33 0.516 0.825 Moderate  1:81 synergic effect 41.1523 10000 0.7290.479 Synergic effect  1:243 123.457 123.457 0.281 0.716 Moderate 1:1synergic effect 123.457 370.37 0.359 0.653 Synergic effect 1:3 123.45710000 0.72 0.58 Synergic effect  1:81 370.37 1.52416 0.558 0.554Synergic effect 1:0 370.37 4.57247 0.581 0.508 Synergic effect   1:0.01370.37 13.7174 0.549 0.576 Synergic effect   1:0.04 370.37 41.1523 0.5790.517 Synergic effect   1:0.11 370.37 123.457 0.683 0.344 Synergiceffect   1:0.33 370.37 370.37 0.718 0.305 Synergic effect 1:1 370.371111.11 0.772 0.253 Strong 1:3 synergic effect 1111.11 13.7174 0.7950.58 Synergic effect   1:0.01

TABLE 11 <Antitumor agent: oxaliplatin, Cancer type: large intestinecancer, Cell line: HCT-116> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 13.7174 3333.33 0.489 0.562 Synergiceffect  1:243.00013 13.7174 10000 0.784 0.104 Strong  1:729.00112synergic effect 41.1523 3333.33 0.488 0.604 Synergic effect  1:80.9998541.1523 10000 0.777 0.129 Strong  1:242.99978 synergic effect 123.4573333.33 0.498 0.666 Synergic effect  1:26.99993 123.457 10000 0.79 0.158Strong  1:80.99986 synergic effect 370.37 1.52416 0.461 0.539 Synergiceffect 1:0.00412 370.37 4.57247 0.484 0.508 Synergic effect 1:0.01235370.37 13.7174 0.463 0.538 Synergic effect 1:0.03704 370.37 41.15230.483 0.516 Synergic effect 1:0.11111 370.37 123.457 0.509 0.493Synergic effect 1:0.33333 370.37 370.37 0.558 0.453 Synergic effect1:1     370.37 1111.11 0.604 0.439 Synergic effect 1:3     370.373333.33 0.771 0.261 Strong 1:9     synergic effect

TABLE 12 <Antitumor agent: gefitinib, Cancer type: non- small cell lungcancer, Cell line: HCC827> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 13.7174 2.28624 0.215 0.66 Synergiceffect 1:0.16667 13.7174 6.85871 0.477 0.262 Strong 1:0.5   synergiceffect 13.7174 20.5761 0.739 0.125 Strong 1:1.5   synergic effect41.1523 6.85871 0.442 0.382 Synergic effect 1:0.16667 41.1523 20.57610.721 0.154 Strong 1:0.5   synergic effect 41.1523 61.7284 0.798 0.223Strong 1:1.5   synergic effect 123.457 20.5761 0.68 0.248 Strong1:0.16667 synergic effect 123.457 61.7284 0.751 0.364 Synergic effect1:0.5   123.457 185.185 0.797 0.676 Synergic effect 1:1.5   370.3720.5761 0.598 0.63 Synergic effect 1:0.05556 370.37 61.7284 0.662 0.846Moderate 1:0.16667 synergic effect 1111.11 0.762079 0.75 0.321 Synergiceffect 1:0.00069 1111.11 2.28624 0.749 0.332 Synergic effect 1:0.002061111.11 6.85871 0.753 0.346 Synergic effect 1:0.00617 1111.11 20.57610.776 0.345 Synergic effect 1:0.01852 1111.11 61.7284 0.774 0.53Synergic effect 1:0.05556 3333.33 2.28624 0.796 0.654 Synergic effect1:0.00069 3333.33 6.85871 0.787 0.726 Moderate 1:0.00206 synergic effect3333.33 20.5761 0.799 0.699 Synergic effect 1:0.00617

TABLE 13 <Antitumor agent: gemcitabine, Cancer type: large intestinecancer, Cell line: HCT-116> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 13.7174 13.7174 0.767 0.038 Extremelystrong 1:1     synergic effect 41.1523 13.7174 0.697 0.111 Strong1:0.33333 synergic effect 123.457 13.7174 0.736 0.103 Strong 1:0.11111synergic effect 370.37 13.7174 0.598 0.585 Synergic effect 1:0.03704370.37 123.457 0.75 0.528 Synergic effect 1:0.33333 1111.11 4.572470.675 0.641 Synergic effect 1:0.00412 1111.11 13.7174 0.783 0.369Synergic effect 1:0.01235 1111.11 41.1523 0.773 0.455 Synergic effect1:0.03704 1111.11 123.457 0.762 0.713 Moderate 1:0.11111 synergic effect

TABLE 14 <Antitumor agent: gemcitabine, Cancer type: gallbladder cancer,Cell line: TGBC2TKB> Anti- Com- tumor pound agent Concomitant 1 (nM)(nM) Fa CI CI_COMMENT ratio 500.0 62.5 0.660 0.371 Synergic effect1:0.13 500.0 125.0 0.708 0.365 Synergic effect 1:0.25 500.0 250.0 0.7210.450 Synergic effect 1:0.5  500.0 500.0 0.715 0.682 Synergic effect1:1   1000.0 62.5 0.652 0.686 Synergic effect 1:0.06 1000.0 125.0 0.6950.649 Synergic effect 1:0.13 1000.0 250.0 0.700 0.756 Moderate 1:0.25synergic effect

TABLE 15 <Antitumor agent: gemcitabine, Cancer type: non- small celllung cancer, Cell line: NCI-H522> Anti- Com- tumor pound agentConcomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 1250 200 0.391 0.723Moderate 1:0.16 synergic effect 1250 400 0.470 0.595 Synergic effect1:0.32 1250 800 0.567 0.490 Synergic effect 1:0.64 2500 200 0.527 0.435Synergic effect 1:0.08 2500 400 0.602 0.329 Synergic effect 1:0.16 2500800 0.594 0.502 Synergic effect 1:0.32 5000 200 0.578 0.522 Synergiceffect 1:0.04 5000 400 0.644 0.376 Synergic effect 1:0.08 5000 800 0.6270.548 Synergic effect 1:0.16 10000 200 0.618 0.718 Moderate 1:0.02synergic effect 10000 400 0.638 0.675 Synergic effect 1:0.04

TABLE 16 <Antitumor agent: gemcitabine, Cancer type: epidermal cancer,Cell line: A431> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 13.7174 123.457 0.649 0.429 Synergic effect1:9.00003 41.1523 370.37 0.8 0.469 Synergic effect 1:8.99998 123.457123.457 0.59 0.62 Synergic effect 1:1     370.37 123.457 0.566 0.767Moderate 1:0.33333 synergic effect 1111.11 123.457 0.606 0.781 Moderate1:0.11111 synergic effect

TABLE 17 <Antitumor agent: cisplatin, Cancer type: small cell lungcancer, Cell line: NCI-H69> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 1000 625 0.515 0.787 Moderate 1:0.63synergic effect 1000 5000 0.798 0.791 Moderate 1:5   synergic effect1000 10000 0.868 0.847 Moderate 1:10  synergic effect 2000 625 0.7170.582 Synergic effect 1:0.31 2000 1250 0.694 0.783 Moderate 1:0.63synergic effect 2000 2500 0.785 0.679 Synergic effect 1:1.25 2000 50000.847 0.681 Synergic effect 1:2.5  2000 10000 0.891 0.763 Moderate 1:5  synergic effect

TABLE 18 <Antitumor agent: cisplatin, Cancer type: non- small cell lungcancer, Cell line: A549> Anti- Com- tumor pound agent Concomitant 1 (nM)(nM) Fa CI CI_COMMENT ratio 13.7174 22.8624 0.337 0.149 Strong 1:1.66667synergic effect 13.7174 68.5871 0.321 0.193 Strong 1:5.00001 synergiceffect 13.7174 50000 0.752 0.465 Synergic effect   1:3645.00561 41.152322.8624 0.302 0.519 Synergic effect 1:0.55556 41.1523 68.5871 0.3240.484 Synergic effect 1:1.66667 41.1523 50000 0.705 0.837 Moderate  1:1214.99892 synergic effect 123.457 22.8624 0.507 0.516 Synergiceffect 1:0.18519 123.457 68.5871 0.5 0.54 Synergic effect 1:0.55555123.457 50000 0.763 0.517 Synergic effect  1:404.99931 370.37 22.86240.797 0.293 Strong 1:0.06173 synergic effect 370.37 68.5871 0.763 0.375Synergic effect 1:0.18519 370.37 1851.85 0.666 0.722 Moderate 1:5    synergic effect 370.37 16666.7 0.751 0.558 Synergic effect  1:45.00014

TABLE 19 <Antitumor agent: cisplatin, Cancer type: epidermal cancer,Cell line: KB> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 250 313 0.743 0.816 Moderate 1:1.25 synergic effect250 625 0.871 0.758 Moderate 1:2.5  synergic effect 500 156 0.887 0.608Synergic effect 1:0.31 500 313 0.932 0.546 Synergic effect 1:0.63 500625 0.953 0.568 Synergic effect 1:1.25

TABLE 20 <Antitumor agent: cytarabine, Cancer type: large intestinecancer, Cell line: HCT-116> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 13.7174 41.1523 0.357 0.412 Synergiceffect 1:3.00001 13.7174 123.457 0.574 0.346 Synergic effect 1:9.0000313.7174 370.37 0.722 0.408 Synergic effect  1:27.00001 41.1523 41.15230.369 0.447 Synergic effect 1:1     41.1523 123.457 0.565 0.393 Synergiceffect 1:3     41.1523 370.37 0.695 0.506 Synergic effect 1:8.99998123.457 41.1523 0.409 0.518 Synergic effect 1:0.33333 123.457 123.4570.533 0.566 Synergic effect 1:1     123.457 370.37 0.755 0.373 Synergiceffect 1:2.99999 370.37 1.52416 0.393 0.774 Moderate 1:0.00412 synergiceffect 370.37 13.7174 0.418 0.778 Moderate 1:0.03704 synergic effect370.37 41.1523 0.65 0.347 Synergic effect 1:0.11111 370.37 123.457 0.780.234 Strong 1:0.33333 synergic effect 1111.11 1.52416 0.725 0.592Synergic effect 1:0.00137 1111.11 4.57247 0.739 0.555 Synergic effect1:0.00412 1111.11 13.7174 0.698 0.687 Synergic effect 1:0.01235 1111.1141.1523 0.77 0.5 Synergic effect 1:0.03704

TABLE 21 <Antitumor agent: cytarabine, Cancer type: epidermal cancer,Cell line: A431> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 13.7174 370.37 0.557 0.831 Moderate  1:27.00001synergic effect 13.7174 1111.11 0.769 0.55 Synergic effect  1:81.0000441.1523 370.37 0.56 0.82 Moderate 1:8.99998 synergic effect 41.15231111.11 0.769 0.552 Synergic effect  1:26.99995 123.457 1111.11 0.740.712 Moderate 1:8.99998 synergic effect 370.37 370.37 0.594 0.706Moderate 1:1     synergic effect 1111.11 41.1523 0.325 0.696 Synergiceffect 1:0.03704 3333.33 1.52416 0.552 0.512 Synergic effect 1:0.000463333.33 4.57247 0.527 0.55 Synergic effect 1:0.00137 3333.33 13.71740.596 0.483 Synergic effect 1:0.00412 3333.33 41.1523 0.672 0.425Synergic effect 1:0.01235 3333.33 123.457 0.688 0.481 Synergic effect1:0.03704 3333.33 370.37 0.711 0.636 Synergic effect 1:0.11111

TABLE 22 <Antitumor agent: dasatinib, Cancer type: acute myelocyticleukemia, Cell line: Kasumi-1> Anti- Com- tumor pound agent Concomitant1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 13.7174 0.527 0.265 Strong1:1     synergic effect 13.7174 41.1523 0.628 0.195 Strong 1:3.00001synergic effect 13.7174 123.457 0.666 0.298 Strong 1:9.00003 synergiceffect 13.7174 370.37 0.668 0.793 Moderate  1:27.00001 synergic effect41.1523 13.7174 0.534 0.385 Synergic effect 1:0.33333 41.1523 41.15230.602 0.368 Synergic effect 1:1     41.1523 123.457 0.648 0.462 Synergiceffect 1:3     123.457 13.7174 0.556 0.701 Moderate 1:0.11111 synergiceffect 123.457 41.1523 0.683 0.383 Synergic effect 1:0.33333 123.457123.457 0.65 0.699 Synergic effect 1:1     123.457 370.37 0.711 0.665Synergic effect 1:2.99999 370.37 41.1523 0.779 0.57 Synergic effect1:0.11111 370.37 123.457 0.794 0.536 Synergic effect 1:0.33333 370.37370.37 0.8 0.566 Synergic effect 1:1    

TABLE 23 <Antitumor agent: doxorubicin, Cancer type: small cell lungcancer, Cell line: SBC-1> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 500.0 62.5 0.789 0.542 Synergic effect1:0.13 500.0 125.0 0.886 0.509 Synergic effect 1:0.25 1000.0 15.6 0.6470.584 Synergic effect 1:0.02 1000.0 31.3 0.826 0.300 Synergic effect1:0.03 1000.0 62.5 0.906 0.244 Strong 1:0.06 synergic effect 1000.0125.0 0.927 0.339 Synergic effect 1:0.13 2000.0 7.8 0.710 0.592 Synergiceffect  1:0.0039 2000.0 15.6 0.770 0.474 Synergic effect 1:0.01 2000.031.3 0.826 0.412 Synergic effect 1:0.02 2000.0 62.5 0.866 0.437 Synergiceffect 1:0.03 2000.0 125.0 0.913 0.449 Synergic effect 1:0.06

TABLE 24 <Antitumor agent: doxorubicin, Cancer type: large intestinecancer, Cell line: HCT-116> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 13.7174 41.1523 0.389 0.356 Synergiceffect 1:3.00001 13.7174 123.457 0.581 0.502 Synergic effect 1:9.0000313.7174 370.37 0.763 0.69 Synergic effect  1:27.00001 41.1523 41.15230.433 0.348 Synergic effect 1:1     41.1523 123.457 0.525 0.65 Synergiceffect 1:3     123.457 41.1523 0.408 0.534 Synergic effect 1:0.33333123.457 123.457 0.537 0.719 Moderate 1:1     synergic effect 370.3713.7174 0.451 0.674 Synergic effect 1:0.03704 370.37 41.1523 0.605 0.493Synergic effect 1:0.11111 370.37 123.457 0.618 0.753 Moderate 1:0.33333synergic effect 1111.11 1.52416 0.737 0.618 Synergic effect 1:0.001371111.11 4.57247 0.706 0.713 Moderate 1:0.00412 synergic effect 1111.1113.7174 0.712 0.717 Moderate 1:0.01235 synergic effect 1111.11 41.15230.705 0.804 Moderate 1:0.03704 synergic effect

TABLE 25 <Antitumor agent: docetaxel, Cancer type: stomach cancer, Cellline: NCI-N87> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 100 4 0.568 0.807 Moderate 1:0.04 synergic effect100 8 0.707 0.716 Moderate 1:0.08 synergic effect 200 4 0.731 0.697Synergic effect 1:0.02 200 8 0.792 0.683 Synergic effect 1:0.04 200 160.848 0.709 Moderate 1:0.08 synergic effect 400 4 0.812 0.845 Moderate1:0.01 synergic effect 400 8 0.85 0.792 Moderate 1:0.02 synergic effect400 16 0.879 0.816 Moderate 1:0.04 synergic effect

TABLE 26 <Antitumor agent: docetaxel, Cancer type: large intestinecancer, Cell line: HCT-116> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 13.7174 0.457247 0.345 0.761 Moderate1:0.03333 synergic effect 13.7174 1.37174 0.691 0.21 Strong 1:0.1  synergic effect 13.7174 4.11523 0.791 0.257 Strong 1:0.3   synergiceffect 41.1523 1.37174 0.71 0.206 Strong 1:0.03333 synergic effect41.1523 4.11523 0.789 0.279 Strong 1:0.1   synergic effect 123.4571.37174 0.651 0.407 Synergic effect 1:0.01111 370.37 1.37174 0.758 0.374Synergic effect 1:0.0037  1111.11 0.152416 0.787 0.679 Synergic effect1:0.00014

TABLE 27 <Antitumor agent: docetaxel, Cancer type: non-small cell lungcancer, Cell line: NCI-H226> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 500 1.25 0.640 0.265 Strong  1:0.0025synergic effect 500 2.50 0.723 0.195 Strong 1:0.01 synergic effect 5005.00 0.803 0.135 Strong 1:0.01 synergic effect 500 10.00 0.852 0.110Strong 1:0.02 synergic effect 500 20.00 0.855 0.157 Strong 1:0.04synergic effect 1000 1.25 0.538 0.771 Moderate  1:0.0013 synergic effect2000 1.25 0.673 0.710 Moderate   1:0.00063 synergic effect

TABLE 28 <Antitumor agent: docetaxel, Cancer type: epidermal cancer,Cell line: A431> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 13.7174 0.457247 0.281 0.681 Synergic effect1:0.03333 13.7174 1.37174 0.618 0.129 Strong 1:0.1   synergic effect13.7174 4.11523 0.766 0.097 Extremely strong 1:0.3   synergic effect41.1523 0.457247 0.281 0.705 Moderate 1:0.01111 synergic effect 41.15231.37174 0.645 0.108 Strong 1:0.03333 synergic effect 41.1523 4.115230.751 0.116 Strong 1:0.1   synergic effect 123.457 1.37174 0.604 0.167Strong 1:0.01111 synergic effect 123.457 4.11523 0.724 0.162 Strong1:0.03333 synergic effect 370.37 1.37174 0.435 0.693 Synergic effect1:0.0037  370.37 4.11523 0.589 0.56 Synergic effect 1:0.01111 3333.330.152416 0.653 0.562 Synergic effect 1:0.00005 3333.33 0.457247 0.6630.555 Synergic effect 1:0.00014 3333.33 1.37174 0.672 0.584 Synergiceffect 1:0.00041 3333.33 4.11523 0.709 0.59 Synergic effect 1:0.00123

TABLE 29 <Antitumor agent: paclitaxel, Cancer type: large intestinecancer, Cell line: HCT-116> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 13.7174 4.11523 0.651 0.313 Synergiceffect 1:0.3   41.1523 4.11523 0.625 0.38 Synergic effect 1:0.1  123.457 4.11523 0.615 0.454 Synergic effect 1:0.03333 370.37 4.115230.598 0.667 Synergic effect 1:0.01111 1111.11 0.152416 0.601 0.777Moderate 1:0.00014 synergic effect 1111.11 1.37174 0.637 0.778 Moderate1:0.00123 synergic effect 1111.11 4.11523 0.79 0.469 Synergic effect1:0.0037 

TABLE 30 <Antitumor agent: paclitaxel, Cancer type: non-small cell lungcancer, Cell line: NCI-H2170> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 100 2.00 0.574 0.669 Synergic effect1:0.02 100 4.00 0.746 0.528 Synergic effect 1:0.04 100 8.00 0.821 0.579Synergic effect 1:0.08 200 2.00 0.753 0.576 Synergic effect 1:0.01 2004.00 0.832 0.507 Synergic effect 1:0.02 200 8.00 0.891 0.475 Synergiceffect 1:0.04 400 2.00 0.871 0.590 Synergic effect 1:0.01 400 4.00 0.8920.577 Synergic effect 1:0.01 400 8.00 0.912 0.593 Synergic effect 1:0.02

TABLE 31 <Antitumor agent: paclitaxel, Cancer type: epidermal cancer,Cell line: A431> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 13.7174 4.11523 0.675 0.281 Strong 1:0.3 synergiceffect 41.1523 4.11523 0.643 0.357 Synergic effect 1:0.1 41.1523 12.34570.777 0.367 Synergic effect 1:0.3 123.457 4.11523 0.636 0.386 Synergiceffect   1:0.03333 123.457 12.3457 0.8 0.3 Synergic effect 1:0.1 370.374.11523 0.553 0.714 Moderate   1:0.01111 synergic effect 370.37 12.34570.766 0.432 Synergic effect   1:0.03333

TABLE 32 <Antitumor agent: vemurafenib, Cancer type: malignant melanoma,Cell line: A375> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 13.7174 123.457 0.367 0.651 Synergic effect1:9.00003 13.7174 370.37 0.494 0.768 Moderate  1:27.00001 synergiceffect 41.1523 123.457 0.343 0.84 Moderate 1:3     synergic effect41.1523 370.37 0.492 0.811 Moderate 1:8.99998 synergic effect

TABLE 33 <Antitumor agent: pemetrexed, Cancer type: large intestinecancer, Cell line: HCT-116> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 13.7174 123.457 0.215 0.386 Synergiceffect 1:9.00003 13.7174 370.37 0.436 0.238 Strong  1:27.00001 synergiceffect 13.7174 1111.11 0.534 0.379 Synergic effect  1:81.00004 13.71743333.33 0.623 0.643 Synergic effect  1:243.00013 41.1523 370.37 0.3880.358 Synergic effect 1:8.99998 41.1523 1111.11 0.526 0.424 Synergiceffect  1:26.99995 41.1523 3333.33 0.621 0.672 Synergic effect 1:80.99985 123.457 1111.11 0.484 0.633 Synergic effect 1:8.99993 370.371.52416 0.337 0.662 Synergic effect 1:0.00412 370.37 4.57247 0.387 0.565Synergic effect 1:0.01235 370.37 13.7174 0.278 0.835 Moderate 1:0.03704synergic effect 370.37 41.1523 0.33 0.724 Moderate 1:0.11111 synergiceffect 370.37 123.457 0.324 0.84 Moderate 1:0.33333 synergic effect370.37 370.37 0.499 0.55 Synergic effect 1:1     1111.11 1.52416 0.7260.578 Synergic effect 1:0.00137 1111.11 4.57247 0.714 0.605 Synergiceffect 1:0.00412 1111.11 13.7174 0.729 0.573 Synergic effect 1:0.012351111.11 41.1523 0.745 0.541 Synergic effect 1:0.03704 1111.11 123.4570.75 0.537 Synergic effect 1:0.11111 1111.11 370.37 0.764 0.524 Synergiceffect 1:0.33333 1111.11 1111.11 0.721 0.697 Synergic effect 1:1    1111.11 3333.33 0.749 0.79 Moderate 1:3     synergic effect

TABLE 34 <Antitumor agent: pemetrexed, Cancer type: epidermal cancer,Cell line: A431> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 13.7174 123.457 0.554 0.273 Strong 1:9.00003synergic effect 13.7174 370.37 0.638 0.38 Synergic effect  1:27.0000113.7174 1111.11 0.697 0.636 Synergic effect  1:81.00004 41.1523 123.4570.509 0.409 Synergic effect 1:3     41.1523 370.37 0.617 0.466 Synergiceffect 1:8.99998 3333.33 1.52416 0.536 0.551 Synergic effect 1:0.000463333.33 4.57247 0.554 0.537 Synergic effect 1:0.00137 3333.33 13.71740.54 0.576 Synergic effect 1:0.00412 3333.33 41.1523 0.534 0.657Synergic effect 1:0.01235 3333.33 123.457 0.565 0.761 Moderate 1:0.03704synergic effect 3333.33 370.37 0.656 0.744 Moderate 1:0.11111 synergiceffect

TABLE 35 <Antitumor agent: bortezomib, Cancer type: multiple myeloma,Cell line: RPMI-8226> Anti- Com- tumor pound agent Concomitant 1 (nM)(nM) Fa CI CI_COMMEMT ratio 400 0.5 0.4 0.832 Moderate 1:0.00125synergic effect 800 0.5 0.75 0.662 Synergic effect 1:0.00063 800 0.80.75 0.721 Moderate 1:0.001  synergic effect 800 1 0.77 0.719 Moderate1:0.00125 synergic effect

TABLE 36 <Antitumor agent: mitomycin C, Cancer type: large intestinecancer, Cell line: HCT-116> Anti- Com- tumor pound agent Concomitant 1(nM) (nM) Fa CI CI_COMMENT ratio 500.0 12.5 0.879 0.757 Moderate 1:0.025synergic effect

TABLE 37 <Antitumor agent: lapatinib, Cancer type: stomach cancer, Cellline: NCI-N87> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 250 3.90625 0.728 0.658 Synergic effect 1:0.016 2507.8125 0.746 0.692 Synergic effect 1:0.031 250 15.625 0.784 0.707Moderate 1:0.063 synergic effect 250 31.25 0.810 0.818 Moderate 1:0.125synergic effect

TABLE 38 <Antitumor agent: lapatinib, Cancer type: breast cancer, Cellline: UACC-893> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM) FaCI CI_COMMENT ratio 1000 62.5 0.590 0.511 Synergic effect 1:0.06 1000125 0.643 0.362 Synergic effect 1:0.13 1000 250 0.629 0.613 Synergiceffect 1:0.25 1000 500 0.715 0.494 Synergic effect 1:0.5  1000 10000.726 0.848 Moderate 1:1   synergic effect 2000 62.5 0.665 0.344Synergic effect 1:0.03 2000 125 0.710 0.246 Strong 1:0.06 synergiceffect 2000 250 0.737 0.263 Strong 1:0.13 synergic effect 2000 500 0.7490.403 Synergic effect 1:0.25 2000 1000 0.761 0.661 Synergic effect1:0.5  4000 62.5 0.708 0.333 Synergic effect 1:0.02 4000 125 0.709 0.384Synergic effect 1:0.03 4000 250 0.712 0.480 Synergic effect 1:0.06 4000500 0.746 0.488 Synergic effect 1:0.13 4000 1000 0.783 0.576 Synergiceffect 1:0.25 8000 62.5 0.702 0.666 Synergic effect 1:0.01 8000 1250.722 0.542 Synergic effect 1:0.02 8000 250 0.726 0.611 Synergic effect1:0.03 8000 500 0.754 0.575 Synergic effect 1:0.06 8000 1000 0.775 0.711Moderate 1:0.13 synergic effect

TABLE 39 <Antitumor agent: lenalidomide, Cancer type: multiple myeloma,Cell line: MM.1S> Anti- Com- tumor pound agent Concomitant 1 (nM) (nM)Fa CI CI_COMMENT ratio 13.7174 15.2416 0.227 0.657 Synergic effect1:1.11111 13.7174 45.7247 0.323 0.551 Synergic effect 1:3.33334 13.7174137.174 0.493 0.284 Strong 1:10    synergic effect 13.7174 411.523 0.6180.225 Strong  1:30.00007 synergic effect 13.7174 1234.57 0.735 0.168Strong  1:90.00029 synergic effect 13.7174 3703.7 0.765 0.293 Strong 1:270.00015 synergic effect 13.7174 11111.1 0.776 0.693 Synergic effect 1:810.00044 41.1523 15.2416 0.244 0.806 Moderate 1:0.37037 synergiceffect 41.1523 45.7247 0.376 0.523 Synergic effect 1:1.11111 41.1523137.174 0.536 0.329 Synergic effect 1:3.33333 41.1523 411.523 0.6520.263 Strong 1:10    synergic effect 41.1523 1234.57 0.756 0.206 Strong 1:30.00002 synergic effect 41.1523 3703.7 0.777 0.317 Synergic effect 1:89.99983 123.457 137.174 0.552 0.67 Synergic effect 1:1.11111 123.457411.523 0.693 0.463 Synergic effect 1:3.33333 123.457 1234.57 0.7880.352 Synergic effect 1:10   

Incidentally, gemcitabine exhibited the same synergic effect as inNCI-H522 even in other non-small cell lung cancers (NCI-H441, NCI-H520).Cisplatin exhibited the same synergic effect as in A549 even in othernon-small cell lung cancers (NCI-H2170, NCI-H226, NCI-H441, NCI-H520,NCI-H522, PC-14). Doxorubicin exhibited the same synergic effect as inSBC-1 even in other small cell lung cancers (NCI-N417). Docetaxelexhibited the same synergic effect as in NCI-H226 even in othernon-small cell lung cancers (NCI-H2170). Paclitaxel exhibited the samesynergic effect as in NCI-H2170 even in other non-small cell lungcancers (HCC827, NCI-H1975). Lapatinib exhibited the same synergiceffect as in UACC-893 even in other breast cancers (BT-474, JIMT-1,MDA-MB-361, MDA-MB-453, SK-BR-3, UACC-812).

As described above, it was clearly found that the azabicyclo compound ofthe invention or a salt thereof exhibited a strong synergic effect withextremely various ranges of antitumor agents having different actionmechanisms.

The invention claimed is:
 1. A method for treating a tumor, comprising:administrating3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideor a salt thereof and at least one other antitumor agent selected fromthe group consisting of amrubicin, doxorubicin, cisplatin, oxaliplatin,gemcitabine, cytarabine, pemetrexed, paclitaxel, docetaxel, etoposide,lenalidomide, imatinib, gefitinib, dasatinib, erlotinib, lapatinib, andcrizotinib, wherein the tumor is at least one selected from the groupconsisting of head and neck cancer, esophageal cancer, stomach cancer,duodenal cancer, liver cancer, gallbladder/bile duct cancer, pancreaticcancer, small intestinal cancer, colorectal cancer, colon cancer, rectalcancer, non-small cell lung cancer, small cell lung cancer, breastcancer, ovarian cancer, cervical cancer, uterine corpus cancer, kidneycancer, bladder cancer, prostate cancer, malignant melanoma, epidermalcancer, multiple myeloma, large intestine cancer, and acute myelocyticleukemia.
 2. The method of claim 1, wherein3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideor its salt and the other antitumor agent are administered to a cancerpatient simultaneously or separately at an interval.
 3. A method fortreating a tumor, comprising: administering3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideor a salt thereof, and at least one other antitumor agent, incombination, to a patient in need thereof, wherein the at least oneother antitumor agent is selected from the group consisting ofamrubicin, doxorubicin, cisplatin, oxaliplatin, gemcitabine, cytarabine,pemetrexed, paclitaxel, docetaxel, etoposide, lenalidomide, imatinib,gefitinib, dasatinib, erlotinib, lapatinib, and crizotinib, wherein thetumor is at least one selected from the group consisting of head andneck cancer, esophageal cancer, stomach cancer, duodenal cancer, livercancer, gallbladder/bile duct cancer, pancreatic cancer, smallintestinal cancer, colorectal cancer, colon cancer, rectal cancer,non-small cell lung cancer, small cell lung cancer, breast cancer,ovarian cancer, cervical cancer, uterine corpus cancer, kidney cancer,bladder cancer, prostate cancer, malignant melanoma, epidermal cancer,multiple myeloma, large intestine cancer, and acute myelocytic leukemia.4. The method of claim 1, wherein3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideor its salt and the other antitumor agent are administered to a cancerpatient simultaneously.
 5. The method of claim 1, wherein3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideor its salt and the other antitumor agent are administered to a cancerpatient separately.
 6. The method of claim 1, wherein the tumor is atleast one selected from the group consisting of non-small cell lungcancer, stomach cancer, epidermal cancer, malignant melanoma, acutemyelocytic leukemia, large intestine cancer, gallbladder cancer, smallcell lung cancer, multiple myeloma, and breast cancer.
 7. The method ofclaim 1, wherein a molar amount ratio of3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideto the at least one other antitumor agent is from 1:0.00014 to
 3645. 8.The method of claim 6, wherein a molar amount ratio of3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideto the at least one other antitumor agent is from 1:0.00014 to
 3645. 9.The method of claim 1, wherein the at least one other antitumor agent isat least one of docetaxel and paclitaxel, and a molar amount ratio of3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideto the at least one other antitumor agent is from 1:0.00014 to 0.3. 10.The method of claim 1, wherein the tumor is at least one selected fromthe group consisting of stomach cancer, large intestine cancer,non-small cell lung cancer, and epidermal cancer, the at least one otherantitumor agent is docetaxel, and a molar amount ratio of3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideto the at least one other antitumor agent is from 1:0.00014 to 0.3. 11.The method of claim 2, wherein the tumor is at least one selected fromthe group consisting of stomach cancer, large intestine cancer,non-small cell lung cancer, and epidermal cancer, the at least one otherantitumor agent is docetaxel, and a molar amount ratio of3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideto the at least one other antitumor agent is from 1:0.00014 to 0.3. 12.The method of claim 4, wherein the tumor is at least one selected fromthe group consisting of stomach cancer, large intestine cancer,non-small cell lung cancer, and epidermal cancer, the at least one otherantitumor agent is docetaxel, and a molar amount ratio of3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideto the at least one other antitumor agent is from 1:0.00014 to 0.3. 13.The method of claim 5, wherein the tumor is at least one selected fromthe group consisting of stomach cancer, large intestine cancer,non-small cell lung cancer, and epidermal cancer, the at least one otherantitumor agent is docetaxel, and a molar amount ratio of3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideto the at least one other antitumor agent is from 1:0.00014 to 0.3. 14.The method of claim 1, wherein the salt of3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamideis at least one selected from the group consisting of an acid additionsalt of an inorganic acid, an acid additional salt of an organic acid, asalt of an inorganic base, a salt of an organic base, a salt of a basicamino acid, and an ammonium salt.